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LETTER FROM THE EDITOR Welcome to the second edition of Cardiometabolic Chronicle. As this publication continues to move forward and expand, we aim to include a variety of topics that reflect some of the most important challenges, advances, and opportunities in the field of cardiometabolic health. At our 13th Annual conference, our pre-conference Women’s Health Summit will explore some of the unique cardiometabolic risk factors in women, including adverse pregnancy outcomes and polycystic ovarian syndrome (PCOS). As experts debate a name change for PCOS, to better reflect both the metabolic and reproductive features, this issue discusses the link between PCOS and cardiometabolic disease, and the need for strategies to control cardiometabolic risk in women with PCOS. Despite the considerable progress made in reducing blood pressure and cholesterol, management of obesity remains a significant public health challenge. An article by our partner Cardiology Today examines how the increased prevalence of obesity is impacting cardiovascular disease risk. In this article, key opinion leaders and experts highlight the association between obesity and cardiovascular disease, and outline strategies for successful weight loss to combat the obesity epidemic. Aggressive and early lowering of low-density lipoprotein cholesterol (LDL-C) has emerged as an important approach in controlling atherosclerotic cardiovascular disease risk (ASCVD). The advent of new non-statin therapies is a significant landmark in managing hypercholesterolemia, particularly in high-risk patients with comorbid type 2 diabetes and clinical ASCVD. Our next featured article assesses current and emerging non-statin therapies and the evidence for aggressive LDL-C lowering in atherosclerosis. This issue will further explore the challenges in the management of diabetic kidney disease (DKD). Despite optimal blood glucose control and therapy with RAAS inhibitors, many patients ultimately progress to kidney failure. The featured article focuses on the latest clinical results with promising agents in DKD, including GLP-1 RAs, SGLT-2 inhibitors, and additional potential targets. The Expert Spotlight features Dr. C. Ronald Kahn, a world-renowned researcher in insulin signaling and insulin resistance, and the keynote presenter at the 13th Annual CMHC conference. Our interview with Dr. Kahn highlights the current state of the field, and his own personal journey. The Patient Perspective, conducted in collaboration with the National Stroke Association, emphasizes the importance of controlling cardiometabolic risk factors for stroke prevention and management, through a compelling patient story. We hope that you enjoy this issue of Cardiometabolic Chronicle, and we thank you for your continuous support and engagement.

Shpetim Karandrea, PhD Editorial Director

Table of contents Featured Articles

• Cardiometabolic Risk in PCOS: Beyond the Reproductive Features

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• Obesity slowly undoing progress made in decreasing CVD • Focusing on Non-Statin Therapies for Lowering LDL-Cholesterol

• More than the RAAS Blockade: Emerging Therapeutic Approaches for DKD Management

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Expert Spotlight

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C. Ronald Kahn, MD

Patient Perspective Wake-Up Call

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Pulse • The Burden of the Prior Authorization Process • The fine line between ‘athlete’s heart’ and structural heart disease

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• A yogurt a day?

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• A tailored letter improves the weight management in women with GDM

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• Google predicts heart attacks through eyes Drug Pipeline Summaries

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Cardiometabolic News

• FDA panel recommends approval of a 90-day implantable CGM

• FDA approves first interoperable CGM

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• FDA approves sodium zirconium cyclosilicate for the treatment of hyperkalemia

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Editorial Director:

Shpetim Karandrea, PhD

Executive Director:

Amanda Jamrogiewicz, CHCP

Art Director:

Jose Wong

Editorial Board:

Erin Franceschini, M.S. Jessica Schumacher Sarenka Smith

• SGLT-2 inhibitors and GLP-1 RAs associated with improved survival in T2D

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• Canakinumab fails to prevent progression from prediabetes to diabetes

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Elizabeth Wheeler

• PCSK9 inhibitor alirocumab reduces CV events after ACS

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• Barbershop-based intervention reduces hypertension in black men

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Marketing & Creative Director:

Advertising & Custom Communications: Kathleen Powell Publisher: Cardiometabolic Health Congress, 1801 N. Military Trail, Ste 200, Boca Raton, FL 33431

Disclaimer: Cardiometabolic Chronicle is published by Cardiometabolic Health Congress. The ideas and opinions expressed in Cardiometabolic Chronicle do not necessarily reflect those of Cardiometabolic Health Congress, its faculty, or its affiliates. The mention of any company, product, service, or therapy in this publication should not be construed as an endorsement of any kind. The information contained in this publication is provided solely for educational purposes. It is the responsibility of the treating physician or other healthcare provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any product or therapy. Cardiometabolic Chronicle, Cardiometabolic Health Congress, its faculty, and its affiliates assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

• Semaglutide may help obese people lose weight

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• Biomarkers improve CV risk assessment in older adults

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• ACP recommends less aggressive HbA1c targets

DIABETES by numbers

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CVD by numbers

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Cardiometabolic Risk in PCOS: Beyond the Reproductive Features By Editorial Board

Focusing on the metabolic phenotype of PCOS Polycystic Ovarian Syndrome (PCOS) is one of the most common endocrine disorders that affects women of reproductive age and is characterized by hyperandrogenism, menstrual irregularity, and polycystic ovaries.1 PCOS is a multi-faceted disease, and although its pathophysiology is not clear, it includes increased ovarian steroid hormone production, defective insulin signaling, as well as genetic and environmental factors.2 Besides the well-defined reproductive phenotype, it is now widely recognized that PCOS also displays a metabolic phenotype.1 As a result, the clinical features reflect the heterogenous basis of the disease. The symptoms include hyperandrogenism, menstrual irregularity, polycystic ovaries, chronic anovulation, but also insulin resistance, glucose intolerance, and dyslipidemia. Metabolic syndrome (MetS) is a cluster of different disease states, such as hypertension, type 2 diabetes, obesity, and dyslipidemia, which are highly associated with PCOS. In the United States, obesity affects 80% of women with PCOS, which corresponds with the rise of the obesity epidemic.3 Although it is unclear whether obesity causes PCOS, it can exacerbate the clinical features of the disease, particularly those related to MetS.3 Decreased insulin sensitivity is a hallmark of PCOS, ever since studies have reported post-receptor binding defects in insulin signaling consisting of increased serine phosphorylation of the insulin receptor and downstream molecules, such as insulin receptor substrate-1 (IRS-1) in women with PCOS.4,5 The decreased insulin sensitivity (or insulin resistance) leads to decreased uptake of glucose in target tissues, and failure of insulin to adequately suppress hepatic gluconeogenesis.1 As a result, insulin resistance increases the risk of impaired glucose tolerance and type

2 diabetes in women with PCOS. Research has shown that the prevalence of impaired glucose tolerance is 25-35% and that of type 2 diabetes is 4-10% in women with PCOS.6,7 In addition, women with PCOS have impaired pancreatic β-cell function, leading to decreased glucose-stimulated insulin secretion.6,8 It is now widely accepted that β-cell dysfunction, in addition to insulin resistance, are two of the most important pathophysiologies leading to the development of type 2 diabetes. Obesity plays a role in the metabolic dysfunctions of PCOS, however; insulin resistance, impaired glucose tolerance, and type 2 diabetes can occur independent of obesity, as reported in lean women with PCOS.1 Due to these metabolic imbalances, women with PCOS may also be at an increased risk for cardiovascular disease (CVD), although it is unclear whether PCOS independently increases risk of cardiovascular mortality.9 Indeed, PCOS is associated with dyslipidemia, an important risk factor for atherosclerotic cardiovascular disease (ASCVD), independent of age and body mass index.10,11 Despite metabolic abnormalities, the three current diagnostic criteria for PCOS, established by the National Institutes of Health (NIH), the Androgen Excess and PCOS Society, and the Rotterdam conference, do not incorporate the manifestations of the metabolic phenotype.12 This has led to underutilization of metabolic screening, ambiguity about which screening tools to use to assess metabolic dysfunction in PCOS, and lack of uniformity in screening practices among different physician specialties that treat PCOS.13,14 A recent survey from the American College of Obstetricians and Gynecologists (ACOG) reported that less than 20% of physicians screen women with PCOS for diabetes and dyslipidemia.13 Other studies have shown that about 26% of primary care physicians don’t screen for type 2 diabetes in women with PCOS, although this number is much lower for endocrinologists.15 Consensus statements from many professional soci-

eties, such as the Endocrine Society, the Androgen Excess and PCOS Society (AEPCOS), and the Australian PCOS Alliance guidelines, recommend screening for type 2 diabetes of all women with PCOS.16 Most of these recommendations, including the latest provided by the American Association of Clinical Endocrinologist (AACE), American College of Endocrinologist and AE-PCOS Society suggest the use of a 2-hr oral glucose tolerance test (OGTT).16 However, discrepancies still exist about how often to repeat OGTT, how to identify women with PCOS at high-risk for type 2 diabetes, and what test to use to evaluate insulin resistance.1,16 Additionally, questions remain on whether common methods used in clinical practice to assess glucose homeostasis or insulin resistance (such as glycated hemoglobin (HbA1c), fasting blood glucose, fasting insulin, and surrogate measures derived from OGTT) are relevant in PCOS.1,14 Due to the accumulating evidence of the increased metabolic risks and other multi-faceted interactions in PCOS, in 2012, an expert panel sponsored by the National Institutes of Health (NIH) concluded that it is time to give the condition a different name.17 This name would not necessarily focus on one single diagnostic criterion (such as polycystic ovaries), but would encompass the many www.cardiometabolichealth.org

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Cardiometabolic Risk in PCOS: Beyond the Reproductive Features metabolic, hypothalamus-pituitary-adrenal (HPA), and ovarian interactions in PCOS, and properly reflect the progress of the field.17 Experts have suggested the name “Metabolic Reproductive Syndrome”, although a consensus about the formal name change has not yet been reached in the medical community.12 Reducing cardiometabolic risk in PCOS Lifestyle interventions, such as exercise and eating a balanced diet, are considered the first line to control cardiometabolic risk in PCOS, particularly in overweight and obese women. Since obesity is known to exacerbate both the reproductive and metabolic phenotypes of PCOS, lifestyle interventions can control symptoms by decreasing weight.18 In addition to diet and exercise, weight loss achieved by bariatric surgery has been shown to ameliorate the adverse metabolic profile in women with PCOS.19

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receptor agonists (GLP-1 RAs) potentiate the effects of endogenous GLP-1, an incretin hormone that is secreted following a meal bolus. Effects of GLP-1 RAs include stimulation of insulin secretion and inhibition of glucagon release when hyperglycemia is present, delay of gastric emptying, reduction of food intake with associated weight loss, and reduction of fasting and postprandial glucose.20 A study showed that the combination therapy of the GLP-1 RA liraglutide and metformin improved glucose tolerance and insulin resistance in women with PCOS compared to monotherapy, in addition to more weight loss.20 Dipeptidyl peptidase 4 (DPP-4) inhibitors increase the levels of incretins and consequently glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells.21 Since there is decreased β-cell function in PCOS, these agents may improve insulin secretion. Indeed, studies with DDP4 inhibitors alogliptin and sitagliptin have been shown to increase GSIS in women with PCOS.20,21 Another class of anti-hyperglycemic drugs, the sodium glucose cotransporter 2 (SGLT-2) inhibitors, which improve glycemic controls by increasing glucose excretion, are being evaluated in phase 2 (empagliflozin) and phase 3 (dapagliflozin) clinical trials in women with PCOS.22,23

(LDL), very-low density lipoprotein (VLDL), and triglycerides (TG), as well as decreased levels of high-density lipoprotein (HDL).25 Managing CV risk in PCOS patients is recognized in the practice guidelines and recommendations. Statin therapy is a well-recognized treatment option which improves hypercholesterolemia and decreases CV risk by lowering LDL-C levels. 25 Recent studies have shown that statins can lower LDL-C in women with PCOS and support their use for controlling ASCVD risk in this patient population.25 At this point there is very little evidence for the use of newer agents (such as PCSK9 inhibitors) or other lipid-lowering treatments (such as omega-3 fatty acids) for CV risk reduction in this setting.

Insulin resistance plays a pivotal role in PCOS, and the use of insulin sensitizers can be beneficial in decreasing cardiometabolic risk. Metformin, an oral oral-antidiabetic drug that decreases hepatic glucose production and improves insulin sensitivity, has been shown to improve glucose intolerance, insulin resistance, and hyperinsulinemia in women with PCOS, and is recommended in these women who have type 2 diabetes or impaired glucose tolerance.2,18 The use of other insulin sensitizers, such as thiazolidinediones (TZDs) and inositols, is not recommended due lack of efficacy and safety.18 In addition, newer anti-hyperglycemic agents have been evaluated in PCOS. Glucagon-like peptide 1 (GLP-1)

Women with PCOS are at greater risk for ASCVD and having PCOS is considered a risk factor for atherosclerosis.24 Studies have shown that women with PCOS have a greater prevalence of dyslipidemia compared to BMI- and age-matched controls; with increased levels of low-density lipoprotein

Conclusion As the medical community continues to debate a name change for the condition, it is clear that the metabolic phenotype is an important component of PCOS, and experts have suggested a tight link between the metabolic and reproductive features. The high prevalence of cardiometabolic abnormalities puts women with PCOS at risk for developing insulin resistance, obesity, type 2 diabetes, and cardiovascular disease. Proper identification and screening approaches are crucial to identifying women with PCOS who are at an increased risk for metabolic imbalances. Awareness about strategies to decrease the cardiometabolic impacts of PCOS are needed, and clinicians treating PCOS should consider comprehensive and evidence-based approaches to reduce cardiometabolic risk.

References: 1. Diamanti-Kandarakis, Evanthia, and Andrea Dunaif. “Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications.” Endocrine Reviews 33.6 (2012): 9811030. 2. El Hayek, Samer, et al. “Poly cystic ovarian syndrome: an updated overview.” Frontiers in Physiology 7 (2016): 124. 3. Dumesic, Daniel A., et al. “Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome.” Endocrine Reviews 36.5 (2015): 487-525. 4. Dunaif, Andrea, et al. “Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.” The Journal of Clinical Investigation 96.2 (1995): 801810. 5. Dunaif, Andrea, et al. “Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS).” American Journal of PhysiologyEndocrinology and Metabolism 281.2 (2001): E392-E399. 6. Ehrmann, David A., et al. “Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.” Diabetes Care 22.1 (1999): 141-146. 7. Legro, Richard S., et al. “Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.” The Journal of Clinical Endocrinology & Metabolism 84.1 (1999): 165-169. 8. O’Meara, N. M., et al. “Defects in beta-cell function in functional ovarian hyperandrogenism.” The Journal of Clinical Endocrinology & Metabolism 76.5 (1993): 1241-1247. 9. Fauser, Bart CJM, et al. “Consensus on women’s health aspects of polycystic ovary syndrome

(PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.” Fertility and Sterility 97.1 (2012): 28-38. 10. Valkenburg, Olivier, et al. “A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study.” The Journal of Clinical Endocrinology & Metabolism 93.2 (2008): 470-476. 11. Wild, Robert A., et al. “Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society.” The Journal of Clinical Endocrinology & Metabolism 95.5 (2010): 2038-2049. 12. Teede, Helena, et al. “Polycystic ovary syndrome: perceptions and attitudes of women and primary health care physicians on features of PCOS and renaming the syndrome.” The Journal of Clinical Endocrinology & Metabolism 99.1 (2014): E107-E111. 13. Dhesi, Amy S., et al. “Metabolic screening in patients with polycystic ovary syndrome is largely underutilized among obstetrician-gynecologists.” American Journal of Obstetrics & Gynecology 215.5 (2016): 579-e1. 14. Gourgari, Evgenia, Elias Spanakis, and Adrian Sandra Dobs. “Pathophysiology, risk factors, and screening methods for prediabetes in women with polycystic ovary syndrome.” International Journal of Women’s Health 8 (2016): 381. 15. Dokras, Anuja, et al. “Gaps in knowledge among physicians regarding diagnostic criteria and management of polycystic ovary syndrome.” Fertility and Sterility 107.6 (2017): 1380-1386. 16. Ollila, M-ME, et al. “Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus—a prospective, population-based cohort study.” Human Reproduction 32.2 (2017): 423-431. 17. Azziz, Ricardo. “Polycystic ovary syndrome: what’s in

a name?.” The Journal of Clinical Endocrinology & Metabolism 99.4 (2014): 1142-1145. 18. Legro, Richard S., et al. “Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 98.12 (2013): 45654592. 19. Butterworth, James, Jean Deguara, and CynthiaMichelle Borg. “Bariatric surgery, polycystic ovary syndrome, and infertility.” Journal of obesity 2016 (2016). 20. Jensterle, Mojca, Katja Goricar, and Andrej Janez. “Add on DPP-4 inhibitor alogliptin alone or in combination with pioglitazone improved β-cell function and insulin sensitivity in metformin treated PCOS.” Endocrine Research 42.4 (2017): 261-268. 21. Ferjan, Simona, Andrej Janez, and Mojca Jensterle. “DPP4 Inhibitor sitagliptin as a potential treatment option in metformin intolerant obese women with polycystic ovary syndrome: a pilot randomized study.” Endocrine Practice (2017). 22. “Empagliflozin vs metformin in PCOS.” ClinicalTrials. gov identifier NCT03008551, available at https:// clinicaltrials.gov/ct2/show/NCT03008551 23. “DAPA, EQW, DAPA/MET ER and PHEN/TPM ER in obese women with polycystic ovary syndrome (PCOS).” ClinicalTrials.gov identifier NCT02635386, available at https://clinicaltrials.gov/ct2/show/ NCT02635386 24. Jellinger, Paul S., et al. “American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.” Endocrine Practice 23.s2 (2017): 1-87. 25. Goodman, Neil F., et al. “American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome-part 1.” Endocrine Practice 21.11 (2015): 1291-1300.

www.cardiometabolichealth.org


Obesity

slowly undoing progress made in decreasing CVD By Darlene Dobkowski, Cardiology Today

Although progress has been made in reducing BP and cholesterol in patients in the United States, obesity, a widespread condition, is halting that progress by increasing the risk for CVD. The prevalence of obesity has risen over the past 3 years, and more than one-third of U.S. adults are estimated to have obesity, according to a 2017 report from the National Forum for Heart Disease and Stroke Prevention. New data from the NHANES surveys showed that agestandardized prevalence of obesity among adults increased from 33.7% in 2007-2008 to 39.6% in 2015-2016. As obesity increases, medical expenditures for the treatment of obesity-related illnesses also rise. In a study published in Clinical Chemistry in 2018, medical expenditures in the United States increased by 29% from 2001 to 2015. “Even though we’re able to make headway in those other risk factors which improve CVD rates, because we, as a society, have not done as great a job as addressing obesity and diabetes, then that’s going to halt the prevention,” Ian Neeland, MD, assistant professor of internal medicine at UT Southwestern Medical Center in Dallas and a Cardiology Today Next Gen Innovator, said in an interview. “It’s certainly one of the main drivers that needs to be further worked on.” Sidney C. Smith, Jr., MD, FAHA, FESC, FACP, MACC, professor of medicine in the division of cardiology at University of North Carolina School of Medicine in Chapel Hill and past president of the AHA and World Heart Federation, agreed. “It’s felt that unless [obesity] can be thwarted, offset, successfully addressed, we have major problems on our hands in terms of heart

attacks and strokes in the future from a cardiovascular standpoint,” he told Cardiology Today. Not only does the relationship between obesity and CVD affect adults, but the risk for CVD in patients with obesity starts in childhood and adolescence. Almost 21% of adolescents aged 12 years to 19 years are obese, and many of these children will continue to have obesity into adulthood, Sadiya S. Khan, MD, MSC, assistant professor of medicine and preventive medicine at Northwestern University School of Medicine, told Cardiology Today. “An understudied question of concern is, as children and adolescents are becoming obese at younger ages, is this burden of cardiovascular disease going to even increase in the coming years?” Khan said. “This further emphasizes the need for primordial prevention starting in childhood throughout adulthood to prevent development of obesity and obesity-related cardiovascular disease.”

The number of patients with CVD will most likely increase over the next decade, as there is a lag between the development of obesity and CVD. The lag may take between 10 years and 12 years, Cardiology Today Editorial Board Member Keith C. Ferdinand, MD, FACC, FAHA, professor of medicine at Tulane University School of Medicine in New Orleans, said in an interview. “This portends, perhaps in the future, with persistent hypertension, increase in new-onset diabetes, increase in overweight and obesity status that we will see perhaps an uptick in cardiovascular mortality going forward,” Ferdinand said. Evidence of association Numerous studies and analyses have established the relationship between obesity and CVD, even as CV-related mortality rates have decreased over time. In a study published in The New England Journal of Medicine in 2007, CHD-related deaths among men and women declined by almost half from 1980 through 2000, mainly due to secondary preventive therapies. In the same time period, diabetes-related deaths increased by 10% and those caused by an increased BMI increased by 8%. Other analyses of cohort-based studies of patients with obesity, including ARIC, CARDIA and the Framingham Heart Study, show a higher rate of stroke, CHD and HF among obese adults compared with those without obesity. Other conditions often linked with obesity include atrial fibrillation, sudden cardiac death, venous thromboembolism, pulmonary embolism and sleep apnea. The increased prevalence of obesity in patients with CVD has affected lifespans in this patient population. In a study published www.cardiometabolichealth.org

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Obesity: slowly undoing progress made in decreasing CVD in JAMA Cardiology in 2018, Khan and colleagues found that both men and women with overweight, obesity and morbid obesity had an increased risk for CVD compared with those with normal weight. Patients with obesity also had shorter longevity. Although the association has been recognized, the mechanisms underlying the association have yet to be determined. Relevant may be risk factors such as hypertension, dyslipidemia, diabetes and excess weight itself, experts told Cardiology Today.

2013, the AHA, ACC and The Obesity Society published prevention guidelines in Circulation on the management of overweight and obesity in adults. The guidelines recognize the association between obesity and CVD and how to properly treat those patients in hopes of achieving optimal CV health.

In the Look AHEAD study published in The New England Journal of Medicine in 2013, 5,145 patients with overweight or obesity and type 2 diabetes were randomly assigned to participate in an intensive lifestyle intervention with increased physical activity and decreased caloric intake or diabetes support and education alone. The intervention group lost more weight than the control group at 1 year (8.6% vs. 0.7%) and at the end of the study (6% vs. 3.5%). Although the intervention group also had greater improvements in all CV risk factors and a greater reduction in glycated hemoglobin, rates of the primary outcome, which was a composite of nonfatal MI, CV-related death, nonfatal stroke or hospitalization for angina, were similar in both groups.

“There is emerging evidence on obesity as an endocrinologic organ, and the inflammatory cytokines and substances that it secretes can injure the heart, therefore affecting the heart’s function and structure,” Neeland said. The location of fat can also be associated with CVD. Central obesity, when fat is located around the abdomen, can not only lead to diabetes, but can cause inflammation from the adipocytes of fat cells. HF is the most prominent condition associated with obesity, although its development is only partially explained by the CV risk factors linked to obesity. Some animal and mechanistic data suggest that obesity has a deleterious effect on the myocardium or is associated with hemodynamic changes. These changes may also be related to fat accumulation in the myocardium itself.

Although a goal of preventing obesity may seem obvious, it is not always discussed with patients. “We generally underperform with regard to addressing obesity with patients, and from providers with whom patients have a trusting relationship and where our medical recommendations have a lot of influence, it’s powerful for our patients to hear from us about the importance of a lifestyle changes and weight loss where appropriate,” Ndumele said. “At many institutions, there are resources often covered by insurance to support weight loss for patients. It’s a topic we can certainly address within our offices and something we can also utilize various resources to help with as well.”

The connection between obesity and CVD may also be explained through mechanisms associated with inflammation, including elevated levels of TNF alpha, CRP, plasminogen activator inhibitor-1 and endothelial cell dysfunction. “That is an area of ongoing work that we don’t have 100% understanding of, but it’s certainly an important focus of investigation,” Chiadi E. Ndumele, MD, MHS, assistant professor of medicine at Johns Hopkins University, told Cardiology Today. Furthermore, obesity is also associated with hypertension. The new American College of Cardiology/American Heart Association hypertension guideline published in November 2017 lowered the threshold for hypertension diagnosis to 130 mm Hg systolic BP/80 mm Hg diastolic BP, which will lead to more Americans receiving a diagnosis of hypertension, much of it driven by obesity. “As the guidelines for hypertension have become more rigorous, therefore, the need to control the increasing obesity rates in the United States will even be more potent because with lower diagnosis of hypertension at 130/80 mm Hg and above in adults, the rates of obesity will increase the rates of hypertension exponentially,” Ferdinand said. The AHA also published a scientific statement in Circulation back in 2006, in which it recognized the relationship between obesity and stroke, CHD and congestive HF, but primarily described it through traditional CVD risk factors and did not emphasize the independent association between obesity and HF. The scientific statement is currently being updated with newer data, Ndumele said. In

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CV risk factors. “I’m usually faced with a patient who is overweight and has CV risk factors that have developed,” Smith said. “I find myself not only treating the hypertension or the dyslipidemia — or if it’s gone even further, they’ve had their heart attack or developed diabetes — but also I am treating the associated risk with obesity, and trying to get the patient to lose weight. There, it becomes difficult depending on where the BMI is.”

Importance of prevention Cardiologists are often the last health care providers to address obesity prevention. Often, this topic is first broached with primary care physicians and/or endocrinologists. However, the cardiologist can play a special role in the opportunity to discuss secondary prevention with patients. “It’s never too late to work on obesity and healthy lifestyle management,” Neeland said. “There are cases where you can cure diabetes and hypertension just through lifestyle changes and weight loss. There’s certainly a lot of opportunity for cardiologists to make major changes in their patients’ lives by addressing obesity, preventing it and then treating it once it occurs.” Focusing on lifestyle modifications in patients with obesity in the setting of CVD has been shown offer to health benefits, especially for

Primordial prevention, which needs to occur before a patient is referred to a cardiologist, is an important approach not only for obesity, but also for the effects associated with it such as CVD. Family history of obesity is a marker for adverse lifestyle in patients, specifically high-calorie meals, sedentary status and potentially hidden genetic factors. “[Therapies] are expensive, and it’s my way of thinking the real approach to this lies in preventing obesity from starting,” Smith said. “The effective strategies there are associated with diet and exercise.” Effective weight loss Lifestyle intervention is the first step in treating patients with obesity, typically focused on increased physical activity and healthy nutrition. “Lifestyle is the most impactful strategy we have because it’s the cheapest, it’s the most effective and efficient, and it has very little risk,” Neeland said. Macronutrients and micronutrients are critical in changing eating habits while controlling the amount of daily caloric intake. A multidisciplinary


Obesity: slowly undoing progress made in decreasing CVD approach to dietary lifestyle changes aids in its success. Involving a physician, a health coach and a nutritionist can also help with patient adherence. If a multidisciplinary approach is not available, patients can download free apps on their phones to help track reductions in calorie intake, increases in physical activity or food logs. The AHA recommends that to improve overall CV health, people should have at least 30 minutes of moderate-intensity aerobic activity at least 5 days per week; or at least 25 minutes of vigorous aerobic activity at least 3 days per week; or a combination of moderate- and vigorous-intensity aerobic activity, as well as moderate to high-intensity muscle-strengthening activity at least 2 days per week for additional health benefits. It also recommends that to improve BP and cholesterol levels, people should have at least 40 minutes of moderate-to-vigorous physical activity three or four times per week. When lifestyle interventions are not effective for a 5% to 10% reduction of body weight, the next strategy is pharmacologic therapy. Currently there are five FDA-approved medications for weight loss: phentermine/ topiramate (Qsymia, Vivus), liraglutide (Saxenda, Novo Nordisk), lorcaserin, (Belviq, Eisai), naltrexone bupropion (Contrave, Orexigen) and orlistat (Alli, GlaxoSmithKline). Although these medications are effective, they do have some side effects and potential risks, so they should serve as aids to lifestyle changes and not be a standalone treatment, experts said. Some side effects include nausea, vomiting, insomnia, headache and pancreatitis. The medications also have contraindications such as pregnancy, multiple drug interactions, drug or alcohol withdrawal and medullary thyroid cancer, Neeland said. “The take-home message therefore is not only do we need prevention, but in those patients who manifest risk reduction, they should be aware of the benefits of modern pharmacotherapy including antihypertensive agents, statins control of dysglycemia, especially with some of the newer diabetic medications such as the GLP-1 agonists and the SGLT2 inhibitors, agents which have been shown in some recent trials to have cardiovascular benefit,” Ferdinand said. The most effective therapy for obesity is bariatric weight-loss surgery, which is reserved for patients at extremely high risk for comorbidities or those who did not lose a substantial amount of weight with lifestyle changes and pharmacotherapy. In a study published in JAMA in January, patients with obesity who underwent bariatric surgery with gastric bypass, laparoscopic banding or laparoscopic sleeve gastrectomy had a reduced risk for all-cause mortality at 4.5 years compared with those who underwent nonsurgical obesity management. In 5-year follow-up data from the STAMPEDE trial, which was presented at the American College of Cardiology Scientific Session in 2016, patients with type 2 diabetes and mild to moderate obesity who underwent bariatric surgery had better control of their glycemic

index compared with those who were treated by an intensive medical therapy approach. Further research More research is needed in this area beyond the mechanism between obesity and CVD, especially in the methods of defining obesity. BMI is not always the most accurate measurement, especially in those who are “skinny fat” or accumulate fat in one area of the body. Understanding the effects of decreasing visceral fat even in the setting of unsubstantial weight loss may help health care professionals guide their patients towards CVD and diabetes prevention. “One of the important things is to understand what are the population-level changes and potential policy changes that will help successfully implement these strategies for the success of primordial prevention on a population level,” Khan said. More research is also needed for future guidelines that define which patients may benefit from the control of CV risk, CV mortality and overall mortality even in the absence of obesity. Although surgical options may be the best treatment option for certain patients with obesity, it is important to not only identify the risks and benefits that each patient may face, but also identify the surgeons with the experience to perform these procedures and what procedures are best for certain patients. One of the most important areas for future research is determining the best methods for successful

weight loss. “Some great work has been done regarding weight loss through behavioral modification in the context of clinical trials,” Ndumele said. “We need better strategies to promote weight loss in real world settings, and not just to promote weight loss, but to maintain weight loss. That’s an area that needs some work.” Cardiologists as patient advocates For patients with overweight and obesity, much of the focus is on weight loss. Cardiologists should support the prevention of not only CVD, but obesity itself while implementing practices of intervention. “We’re seeing the problems with obesity, and it is absolutely critical that we as leaders and those who work with patients who have the morbidity and mortality that’s brought on by obesity become involved in efforts to curtail obesity,” Smith said. Cardiologists should also be aware of patients who are disadvantaged who do not have easy access to healthy foods, which places a patient at risk. “We need to counsel our patients appropriately on how to have health-seeking behaviors that improve access to healthy foods, fresh fruits and vegetables, low-fat dairy products and low saturated protein sources,” Ferdinand said. – by Darlene Dobkowski This article was originally published in Cardiology Today. It is reprinted with permission. For more content, visit Healio. com/Cardiology

The obesity paradox: possible explanations A major topic of discussion has been the obesity paradox, which shows that among patients with CVD, those with obesity may have a survival benefit even though they typically have higher rates for developing the disease. Experts interviewed by Cardiology Today cited the following as important points about the paradox: • Different patient population: Patients with obesity who develop CVD are typically younger and have different risk profiles compared with those at lower weight categories. • Severity of underlying CVD: Although this is difficult to capture in epidemiologic studies, this is a possibility because CVD is linked to drops in weight. The obesity paradox was typically identified in patients with established CVD where there is an association between mortality and morbidity and BMI. More research is needed in patients without CVD to see at what age they develop the disease, their overall burden or mortality and how it affects their lifespans.

• Protection: Adiposity may give patients the metabolic reserve to protect against the wasting associated with CVD. • HFrEF and HFpEF: This paradox is mostly seen in patients with these types of HF. It may be related to a loss of mean muscle mass and overall conditioning. • Paradox after adjustment: Patients with normal or underweight typically smoke more, but after adjusting for issues related to smoking like cancer, age and frailty, the obesity paradox still existed in these patients. The obesity paradox “is real, but it doesn’t necessarily mean that we should be telling people to gain weight,” Ian Neeland, MD, assistant professor of internal medicine at UT Southwestern Medical Center in Dallas and a Cardiology Today Next Gen Innovator, said in an interview. “It might make sense to alert ourselves in the medical community to people who may be underweight or have normal BMI, but still may be at elevated risk for cardiovascular disease.” www.cardiometabolichealth.org

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Obesity: slowly undoing progress made in decreasing CVD

References: Biener, Adam, John Cawley, and Chad Meyerhoefer. “The impact of obesity on medical care costs and labor market outcomes in the US.” Clinical Chemistry 64.1 (2018): 108-117. Ford, Earl S., et al. “Explaining the decrease in US deaths from coronary disease, 1980–2000.” New England Journal of Medicine 356.23 (2007): 2388-2398. Hales, Craig M., et al. “Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016.” JAMA (2018). Jensen, Michael D., et al. “2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.” Journal of the American College of Cardiology 63.25 Part B (2014): 2985-3023. Khan, Sadiya S., et al. “Association of body mass index with lifetime risk of cardiovascular disease and compression of morbidity.” JAMA Cardiology (2018). Look AHEAD Research Group. “Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.” New England Journal of Medicine 369.2 (2013): 145154.

Michalsky, Marc P., et al. “Cardiovascular risk factors after adolescent bariatric surgery.” Pediatrics (2018): e20172485. Poirier, Paul, et al. “Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism.” Circulation 113.6 (2006): 898-918. Reges, Orna, et al. “Association of bariatric surgery using laparoscopic banding, Roux-en-Y gastric bypass, or laparoscopic sleeve gastrectomy vs usual care obesity management with all-cause mortality.” JAMA 319.3 (2018): 279-290. Schauer, Philip R, et. al. “Surgical treatment and medications potentially eradicate diabetes effectively – STAMPEDE.” Featured Clinical Research II. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago. Sidney, Stephen. “Wrong direction: troubling trends in the rate of U.S. cardiovascular disease deaths.” A report from the National Forum for Heart Disease & Stroke Prevention. Available at: www.nationalforum.org.

For more information: Keith C. Ferdinand, MD, FACC, FAHA, can be reached at Tulane University School of Medicine, 1430 Tulane Ave., SL-8548, New Orleans, LA 70112; email: kferdina@tulane.edu. Sadiya S. Khan, MD, MSC, can be reached at NMH/ Arkes Family Pavilion Suite 600, 676 North Saint Clair, Chicago, IL 60611; email: sadiya.khan@fsm.northwestern.edu. Chiadi E. Ndumele, MD, MHS, can be reached at Johns Hopkins Hospital, Carnegie 568, 600 North Wolfe St., Baltimore, MD 21287; email: cndumel2@jhmi.edu. Ian Neeland, MD, can be reached at Clinical Heart Center, 5939 Harry Hines Blvd., 9th Floor, Suite 935, Dallas, TX 75390; email: ian.neeland@utsouthwestern.edu. Sidney C. Smith, Jr., MD, FAHA, FESC, FACP, MACC, can be reached at UNC Heart Center, 300 Meadowmont Village Circle, #313, Chapel Hill, NC 27517; email: scs@med.unc.edu. Disclosures: Khan, Ndumele and Smith report no relevant financial disclosures. Ferdinand reports he is a consultant for Amgen, Boehringer Ingelheim, Novartis, Quantum Genomics and Sanofi. Neeland reports he has received honoraria, consulting, speaking fees and other research support from Boehringer Ingelheim, a research grant from Novo Nordisk and serves on a scientific advisory board for Advanced MR Analytics.


Focusing on Non-Statin Therapies for Lowering LDL-Cholesterol By Editorial Board

Atherosclerotic vascular disease (ASCVD) is the leading cause of death in the United States.1 Approximately 92.1 million people in the US have at least one type of cardiovascular disease (CVD), with more than 45 million additional being at an increased risk for developing CVD within 10 years.1 The economic burden of CVD on the US economy is staggering and currently estimated at $316.1 billion; with this cost expected to rise to $818 billion by 2030.1 Dyslipidemia, which is a key modifiable risk factor for heart disease, encompasses both elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), or triglycerides (TG), and abnormally low levels of lipoproteins such as high-density lipoprotein cholesterol (HDL-C).2 High levels of LDL-C have been shown to be associated with greater ASCVD risk and have traditionally been the primary target of therapy in lipid guidelines.2 Since their introduction more than 30 years ago, statins have been the treatment of choice in lowering cholesterol. High-intensity statins reduce LDL-C by an average of ≥50% and have been shown to reduce ASCVD events in randomized controlled trials.3 The concepts of “treat to target” and “lower is better” have been proposed and debated in the medical literature; although specific LDL-C targets are still controversial. Clinical trials investigating the safety and efficacy of statins provide strong evidence that aiming for and achieving the lowest feasible LDL-C levels is a reasonable treatment goal.2 Results of the IMPROVE-IT trial showed that adding ezetimibe to simvastatin led to incremental lowering of LDL-C levels—even to levels as low as 50 mg/dL—and improved

cardiovascular outcomes compared with simvastatin plus placebo.2 However, statins may not fully eliminate ASCVD risk and residual risk persists among patients receiving maximum tolerated intensity of statins or in patients with statin intolerance or statin resistance. Aggressive LDL-C lowering: non-statin therapies In addition to statin-resistant and statinintolerant patients, statin therapy may not be sufficient to achieve target LDL-C reduction for patients with ASCVD and comorbidities.2 Comorbidities such as diabetes, an ASCVD event while on statin therapy, prior stroke or myocardial infarction (MI), put these patients at increased risk of adverse cardiovascular events; possibly requiring the addition of non-statin agents for secondary prevention if significant LDL-C reduction is not achieved even after optimization of statin therapy.2 The clinical guidelines from the American Diabetes Association support additional lowering of LDL-C in patients with diabetes who have elevated LDL-C levels (≥70 mg/dL) despite maximally tolerated statin therapy.4 In the 2017 update from the American College of Cardiology (ACC) on the role of non-statin therapies for LDL-C lowering, it was suggested that for high-risk individuals (including those with clinical ASCVD, LDL-C ≥190 mg/dL, or with diabetes 40-75 years of age) who may not have an adequate response to statin therapy, the addition of non-statin therapies may be considered.2 The intensity or the specific targets of cholesterol therapy are not fully defined, so much so that the 2013 ACC and American Heart Association (AHA) guidelines for cholesterol treatment did

not support the use of LDL-C target levels for ASCVD prevention.3 However, the approval of new non-statin therapies that aggressively lower LDL-C, such as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, has invigorated the debate about specific LDL-C targets, with many experts advocating for achieving very low levels of LDL-C (below 50 mg/dL and in some cases, ≤20 mg/dL) early in the treatment regimen in order to maximize cardiovascular benefits.5 PCSK9 inhibitors are monoclonal antibodies that block PCSK9 and thus inhibit the ability of PCSK9 to degrade the LDL receptor.2 FDA-approved PCSK9 inhibitors alirocumab and evolocumab have demonstrated their effectiveness in reducing LDL-C levels and ASCVD risk, either alone or in combination with statins.2 Evolocumab and alirocumab are indicated as adjuncts to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD who require additional LDL-C-lowering.2 Evolocumab is also approved for use as an adjunct to other LDL-C-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional LDL-C lowering.2 In the FOURIER trial, the addition of evolocumab to statin therapy led to a 59% mean LDL-C reduction (from a baseline value of 92 mg/dL to 30 mg/dL) in patients with clinical ASCVD and baseline LDL-C ≥70 mg/dL.6 Furthermore, evolocumab treatment significantly reduced the risk of the primary (composite of cardiovascular mortality, myocardial infarction, stroke, hospitalization for unstable angina, or www.cardiometabolichealth.org

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coronary revascularization) and secondary (composite of cardiovascular mortality, myocardial infarction, or stroke) endpoints.6 A secondary analysis of the FOURIER trial showed that evolocumab reduced LDL-C by 66% in patients with a baseline LDL-C ≤70 mg/dL, coupled with significant reductions in both primary and secondary endpoints, demonstrating that aggressive LDL-C lowering conveys cardiovascular benefits in high-risk patients.7 Results from another marque clinical trial, ODYSSEY Outcomes, presented at the ACC 2018 conference, demonstrated the efficacy of alirocumab in lowering LDL-C in patients with a recent acute coronary syndrome event and baseline LDL-C ≥70 mg/dL despite maximal statin therapy. Alirocumab treatment reduced LDL-C levels by 54.7%, as well as significantly reduced the risk of primary endpoint, a composite of coronary heart disease mortality, myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization.8 Results from the FOURIER and ODYSSEY Outcomes studies showed that aggressive LDL-C lowering has tremendous cardiovascular benefits, with excellent safety profiles.8 Due to the strong evidence from the FOURIER trial, recently FDA also approved evolocumab for the prevention of stroke, myocardial infarction, and coronary revascularization in patients with established cardiovascular disease. The efficacy and safety of PCSK9 inhibitors has also been demonstrated in patients with diabetes or dyslipidemia. About 40% of patients in the FOURIER trial were diabetics, and evolocumab also significantly reduced the risk of adverse cardiovascular events, without increasing blood glucose and other glycemic safety parameters in this subset of patients.9 Recently, alirocumab was evaluated in insulintreated type 1 or type 2 diabetic patients with dyslipidemia and high cardiovascular risk (ODYSSEY DM-INSULIN trial), showing significant reduction in LDL-C (a mean 59% reduction) and non-HDL-C in this patient population.10 Another trial, ODYSSEY DMDyslipidemia, demonstrated that alirocumab

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effectively and safely lowered LDL-C and non-HDL-C in individuals with type 2 diabetes and dyslipidemia on maximally tolerated statin therapy.11 Emerging therapies evaluating new molecular targets that can lead to LDL-C reduction in hypercholesterolemic patients are currently being developed in clinical trials. Inclisiran, an siRNA agent that downregulates PCSK9 gene expression, was shown to significantly lower LDL-C (about 50% reduction) in patients at high risk for CVD with elevated LDL-C in a phase II trial.12 Bempedoic acid is an ATP-citrate lyase inhibitor that lowers LDL-C levels by upregulating the LDL receptor.13 Its efficacy in decreasing adverse cardiovascular events in patients with CVD and who are statin- resistance is currently evaluated in a phase III study, and preliminary results demonstrated that it lowers LDL-C by 2028%.13 Evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, recently received FDA-breakthrough therapy designation for HoFH and is also currently being evaluated in a phase II clinical study as a potential LDL-C lowering agent in patients with high-risk of ASCVD an elevated LDL-C despite maximally tolerated statin therapy.14 Gemcabene, an agent that lowers LDL-C and TG by inhibiting liver acetyl CoA carboxylase (ACC) and HMG-CoA Synthase, was shown to lower LDL-C in patients with ASCVD and elevated LDL-C despite optimized statin therapy in a phase II trial.15 In some high-risk patients, particularly those with comorbidities, target LDL-C reduction is not achieved with optimized statin therapy alone, and additional LDL-C lowering may be required. The recent results with non-statin therapies have provided significant evidence towards the early and aggressive lowering of LDL-C therapy, showing that this approach can maximize cardiovascular benefits and is generally well tolerated. The approval of PCSK9 inhibitors has given clinicians more options in decreasing CVD risk in these patients, and additional emerging therapeutics might also be available in the near future.

References: 1. Benjamin, Emelia J., et al. “Heart disease and stroke statistics-2017 update: a report from the American Heart Association.” Circulation 135.10 (2017): e146-e603. 2. Lloyd-Jones, Donald M., et al. “2017 focused update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.” Journal of the American College of Cardiology 70.14 (2017): 1785-1822. 3. Stone, Neil J., et al. “2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines.” Journal of the American College of Cardiology 63.25 Part B (2014): 28892934. 4. American Diabetes Association. “9. Cardiovascular disease and risk management: standards of medical care in diabetes—2018.” Diabetes Care 41.Supplement 1 (2018): S86-S104. 5. Soran, Handrean, Ricardo Dent, and Paul Durrington. “Evidence-based goals in LDL-C reduction.” Clinical Research in Cardiology 106.4 (2017): 237-248. 6. Sabatine, Marc S., et al. “Evolocumab and clinical outcomes in patients with cardiovascular disease.” New England Journal of Medicine 376.18 (2017): 1713-1722. 7. Giugliano, Robert P., et al. “Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.” The Lancet 390.10106 (2017): 1962-1971. 8. Sabouret, Pierre, D. Angoulvant, and A. Pathak. “FOURIER to ODYSSEY: the end of the journey for lipid-lowering therapy trials? Lessons from recent clinical trials with anti-PCSK9 antibodies.” EuroIntervention: Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2018). 9. Chan, Paul, et al. “The ODYSSEY DMDYSLIPIDEMIA trial: confirming the benefits of alirocumab in diabetic mixed dyslipidemia.” Annals of Translational Medicine 5.23 (2017). 10. Leiter, Lawrence A., et al. “Efficacy and safety of alirocumab in insulin–treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM–INSULIN randomized trial.” Diabetes, Obesity and Metabolism 19.12 (2017): 1781-1792. 11. Ray, Kausik K., et al. “Alirocumab vs usual lipid–lowering care as add–on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM–DYSLIPIDEMIA randomized trial.” Diabetes, Obesity and Metabolism 20.6 (2018): 1479-1489. 12. Ray, Kausik K., et al. “Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol.” New England Journal of Medicine 376.15 (2017): 1430-1440. 13. McGowan, Mary, et al. “Bempedoic acid reduces LDL-C and is well-tolerated in patients receiving atorvastatin 80 mg background therapy.” Journal of Clinical Lipidology 11.3 (2017): 838. 14. Dewey, Frederick E., et al. “Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.” New England Journal of Medicine 377.3 (2017): 211-221. 15. Frias, Juan, et al. “Gemcabene add-on therapy to high-and moderate-intensity statin stratums in hypercholesterolemic subjects (ROYAL-1, a Phase 2b Study).” (2017): A23082-A23082.


More than the RAAS Blockade: Emerging Therapeutic Approaches for DKD Management The scope of the problem Diabetic kidney disease (DKD) is one of the most common complications of diabetes, affecting up to 50% of diabetics, and leading to increased morbidity and mortality. DKD is the leading cause of dialysis-dependent chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the US and in most countries.1 The coexistence of diabetes and kidney disease increases the risk of premature mortality and cardiovascular disease (CVD).1 Furthermore, DKD patients have other comorbidities, such as hypertension, obesity, and dyslipidemia, which can also contribute to its incidence and severity.2 As a result, the healthcare costs of DKD are estimated to be $43 billion annually in US, and the overall impacts of the disease are projected to increase.3 Due to the multiple comorbidities in patients with DKD, clinicians have to consider simultaneous approaches to preserve kidney function, including glucose and hypertension control, as well as treatment of dyslipidemia, which complicates the clinical management. Another major challenge in DKD is slowing the progression of the disease, given the very low survival rates in patients with diabetes and advanced-stage kidney disease.4 A great concern remains that despite optimized glycemic and blood pressure control using antihyperglycemic agents and RAAS inhibitors, many DKD patients still progress to kidney failure.4 The multifactorial management of DKD Decreasing the incidence of end-stage renal disease depends on preventing new-onset diabetic nephropathy as well as preventing the progression of established diabetic nephropathy. However, major challenges associated with DKD management currently exist, including early diagnosis of at-risk patients, and lack of specific treatment options.5 DKD is characterized not only by decreased glomerular filtration rate (GFR), but also persistent proteinuria and high blood pressure. Increased intraglomerular capillary pressure has been characterized as one of the underlying pathophysiologies of chronic kidney disease and lowering this pressure has been the target of clinical trials with renin-angiotensin-aldosterone system (RAAS)

inhibitors.6 Indeed, several trials have shown that RAAS inhibitors, particularly angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce kidney disease events in patients with stage 3 CKD who have concurrent diabetes and hypertension.6 As a result, the use of ACE inhibitors or ARBs is recommended to lower hypertension in DKD patients, and they have also been shown to slow DKD progression.7 However, the combination of ACE inhibitors and ARBs is generally contraindicated due to increased risk of renal failure.7 Patients with T2DM have a significantly increased risk of atherosclerotic cardiovascular disease, which should be adequately controlled. Early intensive management of dyslipidemia is warranted to prevent macrovascular disease, and treatment to lower levels of LDL cholesterol is indicated. Current guidelines recommend the use of statins in diabetic patients with non-dialysis dependent CKD, as statins have been shown to decrease albuminuria in these patients.6 Maintaining glycemic goals is crucial in controlling the progression of DKD.7 Due to the plethora of antihyperglycemic drugs, it can be challenging for clinicians to recommend a specific regimen in the context of CKD, since many of these drugs are renally cleared and may require dose adjustments. Additionally, clinical practice guidelines are not specific when it comes to antihyperglycemic medications in DKD patients. Recently, some agents, such as sodium-glucose co-transporter 2 (SGLT-2) inhibitors (empagliflozin and canagliflozin) and the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, in addition to glycemic control, have been shown to improve risk of worsening nephropathy and albuminuria progression in DKD.7 The promise of SGLT-2 inhibitors and GLP-1 receptor agonists Encouraging results stemming from secondary analyses of cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors empagliflozin and canagliflozin, and GLP-1 RA liraglutide suggest that these agents may have a role in the management of DKD. SGLT-2 is a glucose transporter located in the proximal tubule of the kidney that is responsible for 90% of glucose reabsorption. SGLT-2 inhibitors block the reabsorption of glucose in the kidney, thereby

By Editorial Board increasing glucose excretion. In an analysis of prespecified secondary endpoints of the EMPA-REG OUTCOME study, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than placebo when added to standard care.8 Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 patients (18.8%) in the placebo group (hazard ratio, 0.61; P â&#x2030;¤ 0.001). In addition, doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the active treatment group, vs in 60 of 2323 (2.6%) in the placebo group (relative risk reduction of 44%). Renalreplacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group (55% lower relative risk).8 An additional sub-analysis of this trial showed that empagliflozin reduced risk of cardiovascular death, all-cause mortality, and HF hospitalizations in type 2 diabetics with advanced (GFR < 60 mL/min) kidney disease.9 Results from the CANVAS-R trial demonstrated that treatment with SGLT-2 inhibitor canagliflozin was associated with a lower risk of progression of albuminuria, decreased GFR, need for renal-replacement therapy, or renal-caused mortality.10 However, renal effects were not the primary endpoint in these trials or they may not have been sufficiently powered to draw definitive conclusions, emphasizing a need for additional studies with a greater proportion of DKD patients. Indeed, larger clinical trials to evaluate whether canagliflozin, empagliflozin, and another SGLT-2 inhibitor, dapagliflozin, confer renoprotective effects in T2DM patients with CKD are currently ongoing. A prespecified secondary analysis of the LEADER trial showed that liraglutide significantly reduced the risk of adverse renal outcomes compared with placebo in patients with T2DM and high cardiovascular risk who were receiving usual care.11 These outcomes included a composite of new-onset persistent macroalbuminuria (urinary albumin excretion rate > 300 mg/day), persistent doubling of the serum creatinine level, ESRD, or death due to renal disease. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. At a median follow-up of 3.84 years, 22% fewer patients of 4,668 www.cardiometabolichealth.org

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More than the RAAS Blockade: Emerging Therapeutic Approaches for DKD Management assigned to liraglutide reached the composite endpoint compared with 4672 patients receiving placebo (5.7% vs 7.2%; hazard ratio, 0.78; P = 0.003). According to the authors, the lower risk of developing the composite renal outcome with liraglutide was mainly due to a lower rate of new-onset persistent macroalbuminuria, with 26% fewer patients in the liraglutide group developing this complication vs those in the placebo group (3.4% vs 4.6%; HR, 0.74, P = 0.004).11

DKD trial, and the planned FINESSE-HF, will evaluate the role of this agent on reducing the cardiovascular morbidity and mortality in T2DM patients with a DKD diagnosis, and in patients with chronic heart failure with reduced ejection fraction and T2DM with or without CKD, respectively.12 The results from these trials will provide key data about the utility of finerenone in treating DKD and its associated cardiovascular morbidity and mortality.

New frontiers Although ACE inhibitors and ARBs have proven effective in reducing progression to advanced albuminuria in DKD, they do not slow progression to ESRD (ADA Standards of Care 2018). This incomplete effectiveness may be due to lack of inhibition of aldosterone, which has known detrimental effects to kidney function.12 Currently, the therapies to manage DKD mainly include addressing metabolic comorbidities and hypertension, but do not sufficiently address the kidney dysfunction.4,5 Some of these treatments may increase the levels of aldosterone, which in turn can exacerbate proteinuria and kidney damage.12 The results with SGLT-2 inhibitors and GLP-1 RAs, although promising, need to be evaluated in trials where the kidney outcomes are the primary endpoint.4 Additionally, the specific mechanisms of action of the renal benefits of GLP-1 RAs have not been fully elucidated. Due to the insufficiency of current pharmacological treatments, many patients with DKD ultimately progress to kidney failure despite optimal blood pressure and glycemic control, suggesting the need for additional therapies and therapeutic targets to improve this prognosis.4

Blocking the endothelin receptor is another potential new target in DKD. The rationale is that endothelin-1, acting via the endothelin receptor, is a potent mediator of kidney injury in diabetes, and blocking endothelin signaling may improve DKD.14 Indeed, promising results have been shown with endothelin receptor antagonist, atrasentan. This agent reduced proteinuria in patients with T2DM and nephropathy already on optimized ACEi/ ARB therapy in a phase II study.14 In addition, atrasentan has benefits on blood pressure and lipid profile in T2DM patients, which are known risk factors for CKD progression.14 Currently, the effect of atrasentan in reducing the risk of CKD progression in patients with T2DM already on optimized background ACEi/ARB therapy is being evaluated in a phase III trial.15

As a result, several new therapies that target additional pathways involved in ESRD progression are currently in clinical development. Among them, mineralocorticoid receptor antagonists (MRAs) are currently being investigated due to their ability to block aldosterone signaling. Aldosterone acts via the mineralocorticoid receptor to regulate sodium balance but can also cause kidney inflammation and fibrosis.12 Steroidal MRAs, such as spironolactone and eplerenone, have been shown to reduce proteinuria, but they increase hyperkalemia, which can worsen CKD progression.12 In turn, non-steroidal MRA finerenone has decreased risks of hyperkalemia and has been shown to improve kidney outcomes in diabetic patients. The phase IIb trial ARTS-DN (ARTS-Diabetic Nephrophathy) analyzed the safety and efficacy of finerenone in diabetic patients with high or very high albuminuria receiving an ACEi or ARB.13 Results from this trial showed that finerenone decreased albuminuria in a dose-dependent manner with fewer incidents of hyperkalemia compared to placebo.13 The potential of finerenone in the treatment of DKD is currently being investigated in a large phase III trial (FIDELIO-DKD), with the primary endpoint being the composite onset of kidney failure for a follow up period of 48 months.12 Two additional trials, the phase III FIGARO-

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Additionally, several other potential pathways that may play a role in the advancement of DKD, such as immune pathways and inflammation are being investigated in the early phase clinical trials. Immune activation and inflammation have been shown to lead to kidney fibrosis and ultimately kidney failure through a variety of potential pathways: increasing oxidative stress, activation of the JAK/STAT pathway, transcription factors, release of inflammatory cytokines, glycosylation and advanced glycosylation end products (AGE).16 As such, a new wave of agents that target several steps in the immunity and inflammation cascade, such as chemokine receptor antagonists, antioxidants, JAK/STAT inhibitors, glycation and AGE inhibitors, may show promise in DKD treatment. One particular agent, monocyte chemoattractant-1 (MCP-1) receptor antagonist CCX140 reduced albuminuria in T2DM patients on ACEi/ARB therapy, suggesting that this may be a viable treatment target.17 However, the results of these trials, and subsequent larger trials, will determine the utility of these additional targets in DKD treatment. Conclusion The prevalence of DKD has increased in the recent years and it remains a major health problem with significant financial impacts to the US economy. The complicated pathophysiology of the condition and the insufficiency of current treatments are major barriers that clinicians face in reducing DKD progression, morbidity and mortality. The management of hypertension and hyperglycemia, in addition to other cardiometabolic risk factors, play an important role in controlling the incidence or progression of kidney disease in type

2 diabetes. However, even with optimal glycemic and blood pressure control, many patients progress to kidney failure. Newer anti-hyperglycemic agents, such as SGLT-2 inhibitors and GLP-1 RAs have shown promising results in DKD patients. Additionally, mineralocorticoid receptor and endothelin receptor antagonists, as well as agents that target immune activation and inflammation are in clinical development and may provide additional options for the management of DKD in the near future. References: 1. Saran, Rajiv, et al. “US Renal Data System 2016 annual data report: epidemiology of kidney disease in the United States.” American Journal of Kidney Diseases 69.3 (2017): A7-A8. 2. Hall, Michael E., et al. “Obesity, hypertension, and chronic kidney disease.” International Journal of Nephrology and Renovascular Disease 7 (2014): 75. 3. Hoerger, Thomas J., et al. “The future burden of CKD in the United States: a simulation model for the CDC CKD Initiative.” American Journal of Kidney Diseases 65.3 (2015): 403-411. 4. Walther, Carl P., Adam Whaley-Connell, and Sankar D. Navaneethan. “Emerging therapeutic options for managing diabetic kidney disease.” Current Opinion in Nephrology and Hypertension 26.5 (2017): 335-337. 5. Duru, O. Kenrik, et al. “The landscape of diabetic kidney disease in the United States.” Current Diabetes Reports 18.3 (2018): 14. 6. Tuttle, Katherine R., et al. “Diabetic kidney disease: a report from an ADA Consensus Conference.” American Journal of Kidney Diseases 64.4 (2014): 510-533. 7. American Diabetes Association. “10. Microvascular complications and foot care: standards of medical care in diabetes—2018.” Diabetes Care 41.Supplement 1 (2018): S105-S118. 8. Wanner, Christoph, et al. “Empagliflozin and progression of kidney disease in type 2 diabetes.” New England Journal of Medicine 375.4 (2016): 323-334. 9. Wanner, Christoph, et al. “Empagliflozin and clinical outcomes in patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease.” Circulation (2017): CIRCULATION AHA-117. 10. Neal, Bruce, et al. “Canagliflozin and cardiovascular and renal events in type 2 diabetes.” New England Journal of Medicine 377.7 (2017): 644-657. 11. Mann, Johannes Fe, et al. “Liraglutide and renal outcomes in type 2 diabetes.” New England Journal of Medicine 377.9 (2017): 839-848. 12. Dojki, Farheen K., and George Bakris. “Nonsteroidal mineralocorticoid antagonists in diabetic kidney disease.” Current Opinion in Nephrology and Hypertension 26.5 (2017): 368374. 13. Bakris, George L., et al. “Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.” JAMA 314.9 (2015): 884-894. 14. Georgianos, Panagiotis I., and Rajiv Agarwal. “Endothelin A receptor antagonists in diabetic kidney disease.” Current Opinion in Nephrology and Hypertension 26.5 (2017): 338-344. 15. Heerspink, Hiddo JL, et al. “Rationale and protocol of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy.” Diabetes, Obesity and Metabolism (2018). 16. Pichler, Raimund, et al. “Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets.” American Journal of Physiology-Renal Physiology 312.4 (2017): F716-F731. 17. Yap, H. L., A. H. Frankel, and F. W. K. Tam. “Review Article-MCP-1: A Potential Target for Diabetic Microvascular Complications.” Urology and Nephrology Open Access Journal 5.3 (2017): 00171.


E XPE RT SPOTLIGHT

C. Ronald Kahn, MD Dr. C. Ronald Kahn is an expert in diabetes and obesity and a preeminent investigator of insulin signaling and mechanisms of altered signaling in diabetes and metabolic disease. Dr. Kahn is currently the Chief Academic Officer at Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. Dr. Kahn served as Research Director of the Joslin Diabetes Center from 1981 to 2000 and President of Joslin from 2001 to 2007. He has received more than 70 awards and honors and has authored more than 600 original publications and 200 reviews and book chapters. Dr. Kahn will deliver the keynote address at our upcoming annual conference, which will be held October 24-27 in Boston. What inspired you to become a physicianscientist? Growing up, I was always interested in science. My older brother is a PhD scientist. I decided to become a physician as opposed to a PhD because my parents encouraged me to pursue medicine, and I liked the idea. So, I became a physician with the intention of doing both medicine and science, and it has worked out. Who has had the greatest influence on your career? I’ve been fortunate to have had great mentors that have influenced me at different stages of my career. In particular, Dr. Jesse Roth stands out. He was my immediate mentor when I went to the National Institutes of Health as a fellow, and clearly he has had the most influence on my career as a researcher. But I have had other important mentors including Phil Gordon, who have taught me a lot. What area of research in cardiometabolic health interests you most now and why? I’ve always been most interested in the areas of insulin action and insulin resistance. I believe that it is very important to better understand insulin action, and its central role in the pathophysiology of many metabolic diseases, including type 2 diabetes, obesity, metabolic syndrome, non-alcoholic fatty liver disease, polycystic ovarian syndrome and more. Thus, delving deeper into the mechanisms of insulin action and its

searching them out. I’ve always liked the clinical interactions with patients, although it is challenging to balance the demands of basic research and clinical practice. What I’ve always tried to do and also encourage my fellows to do, is to find a way to do clinical work that directly relates to your research interests. In my case, I’ve focused my clinical work in trying to identify patients who have insulin resistance, which is a natural extension of my research efforts. Now I just focus on research.

alterations in these disease states is a terrifically challenging but an important area to get a handle on. What do you think is going to be the next big thing in your field over the next decade? There are a number of developments that are of great interest. One exciting area that several groups are exploring, including our group, is how the microbiome influences insulin sensitivity and cardiometabolic health. Another fascinating topic is the link between insulin resistance, metabolic disease, and brain function, and the potential role of metabolic dysfunction in the pathophysiology of neurological disorders, such Alzheimer’s disease and depression. Understanding that link might be important not only for the cardiometabolic space, but for the behavioral science and psychiatric space as well. What has been the greatest challenge during your professional career? One of the challenging aspects of being an academic is to get the grant support you need to do the research. Simultaneously focusing on your work and funding is challenging, particularly with the shortage of research funding and the strong competition. It is a persistent problem that one must constantly address, no matter how long you are in the field. How do you see the role of the physicianscientist in patient care? It is certainly getting harder for people to be physician-scientists and to be active in both clinical work and be successful in doing research. Opportunities in clinical research maybe easier to come by, but when you do basic research like I do, finding opportunities is harder and one must be proactive in

What do you consider your greatest achievement? I’ve been very excited about many scientific discoveries that we’ve made over the years, but I think that the body of work that I’m really proud of is how we’ve used mouse genetics to identify the role of insulin signaling in each tissue of the body, one tissue at a time. Over the last decade, we have probably made more than 15 different strains of genetically engineered mice, in which we knocked out the insulin receptors in several tissues, including liver, muscle, fat, endothelial cells, and brain. This has helped us get a comprehensive picture of how insulin works tissue by tissue at the whole-body level in a way that can’t be achieved by any other technique. The second thing that I’m extremely proud of are the people that I’ve trained in research. I have now trained probably in excess of 175 MDs and PhD, many of whom have gone to become extremely successful themselves, both in academia as heads of departments, professors, and deans, as well as in the pharmaceutical industry. What are your hobbies outside of research? There are many things that I’m passionate about outside of research. I love to read all kinds of books, both fiction and nonfiction. Pretty much all the time I’m reading a book or occasionally two. In terms of activities, I like to be out either walking, hiking, and sometimes jogging. We have a house on a small lake in Cape Cod, and I enjoy kayaking around that area as well. What is your motto or philosophy? Persistence pays off. Not my unique motto, but it is certainly a motto for a lot of things in life. When you think about what it takes to be successful in any field, whether it is science, medicine, arts, writing, or any career you choose, a great part of it has to do with trying to force yourself to be persistent and not letting any setbacks stop you in achieving your goals and dreams. One must not only keep pushing through adversity, but also at the same time, it is important to figure out what you need to change in order to be successful. www.cardiometabolichealth.org

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Metabolic Syndrome and Related Disorders The only peer-reviewed journal focused on the pathophysiology, recognition, and treatment of metabolic syndrome, a cluster of conditions linked to obesity, type 2 diabetes, cardiovascular disease, stroke, fatty liver, cancer, and other diseases Metabolic Syndrome and Related Disorders is the only peer-reviewed journal focusing solely on the pathophysiology, recognition, and treatment of this major health condition. The Journal meets the imperative for comprehensive research, data, and commentary on metabolic disorder as a suspected precursor to a wide range of diseases, including type 2 diabetes, cardiovascular disease, stroke, cancer, polycystic ovary syndrome, gout, and asthma.

Coverage Includes:

• Insulin resistance • Central obesity • Glucose intolerance • Dyslipidemia with elevated triglycerides • Low HDL-cholesterol • Microalbuminuria • Predominance of small dense LDL-cholesterol particles • Hypertension • Endothelial dysfunction • Oxidative stress • Inflammation • Related disorders of polycystic ovarian syndrome, fatty liver disease (NASH), and gout Editor-in-Chief: Adrian Vella, MD Mayo Clinic College of Medicine, MN

VISIT US ONLINE liebertpub.com/met


PAT I ENT PERSPE CTIVE

Wake-Up Call By Nancy Coulter-Parker

When Robert Reyes had a stroke at age 37, he didn’t expect it to change his life for the better. Robert Reyes admits he wasn’t living the healthiest life when he had a stroke at age 37. “I was living selfishly,” he says. At the time, having a stroke was the farthest thing from his mind. So far, in fact, that when his doctor told him he had high blood pressure, he didn’t take it seriously. Or, when his dentist twice told him they could not put him under anesthetic for a dental procedure because his blood pressure was too high, he was still in denial that anything was wrong. “I had no idea what high blood pressure was until after my stroke. I did not take it seriously. I figured when I’m 60 all this stuff will come back to haunt me, but who cares, I will be free right now,” he explains. And, there were more telltale signs that led up to his stroke. In addition to high blood pressure, he had headaches and random nosebleeds. In general, Reyes felt bad for months on end. “I assumed it was my food and alcohol intake. Now that I know some of the things to look for, I probably would have heeded those warning signs a little sooner.” He also had a family history of diabetes, a disease that increases a person’s stroke risk. Reyes worked as a manager for the Austin, Texas–based Alamo Drafthouse Ritz, a theater that serves beer and food during movies. He had worked there for 13 years

and, over the course of doing so, had developed some great friends but also some not-so-healthy habits: smoking; drinking alcohol, soda, and coffee; not eating healthy; and not exercising. To Reyes’s credit, those habits changed fast. “I’ve given up sodas, alcohol, coffee, and I don’t smoke anymore. It’s a pretty extreme life, and I never thought I would toy with the idea of complete sobriety. I was pretty committed to those vices prestroke, but now I am pretty committed to clean living.” On April 10, 2015, Reyes had a stroke that landed him in the hospital for several weeks and put him on a path to learn to walk and talk again. He spent three months in a wheelchair, and then three months with a walker and cane, until December 2015 when he went to the Star Wars premier with his brother—without his cane. “When I was in the hospital, we made a pact for us to watch Star Wars together when I got out. I didn’t know if I would be walking or not. I made it a personal goal to try to go without a cane the day it premiered.” And so he left his cane at home. “It was crazy. I was happy to be watching Star Wars with my brother, but I was terrified to be without the cane.” At that point, Reyes says, he had a lot of fear, not just about walking, but about what lay ahead and what life would offer him. “Fear after a stroke is a tough mental thing to overcome,” he explains. And, he cautions, it’s easy to get overwhelmed with negativity. For instance, he found that much of the information he read online was negative and did not leave him feeling hopeful about his recovery. “It’s hard to read some of the stuff and think you’ll be trapped inside the house. ‘I’ll never play football again. I’ll never be out

on that trail in the woods again.’” He found himself sinking into depression. Reyes then decided to stop reading negative information online and to try to turn his outlook from one of fear to one of acceptance. It made a huge difference in his recovery. “When I got home, I was so depressed, and typically I’m not that kind of person. I think I made this active decision to be as positive as I could be because if I let myself get stuck in the downward spiral of negative thinking, I was making myself feel horrible.” Reyes explains that these negative feelings are common among stroke survivors. One thing that helped him think positively was to ease off unrealistic recovery deadlines he had set for himself and instead aim for longer-term goals. “I won’t be riding my two-wheel bike around any time soon, but it’s a nice goal to have. But walking without the fear of falling is the first goal,” he explains. “I would love to be going hiking right now, but it’s not a reality. So I can be mad about it or say, “Those trails are going to be there in a year or two when I can walk down a trail.” Part of not rushing the healing process was realizing it was not only OK to accept help from friends and family, but that he needed their help. “The truth of the situation is that I didn’t want help, but there is no way I could have gotten here without help from friends, family, and work.” Reyes ended up finding an Instagram group of young stroke survivors, who had a more positive outlook on recovery, sharing their progress with one another. It also helped that Reyes’s workplace was resoundingly supportive and created a new position for him in the Alamo Drafthouse corporate office. www.cardiometabolichealth.org

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Wake-Up Call

PULSE Blogs

Our CMHC Pulse blog is a biweekly online publication, with posts that highlight current events and contemporary findings in cardiometabolic health. Based on the most recent clinical studies and information, Pulse delivers its readers summaries of the newest available data in heart health, with accompanying graphics and visuals.

As soon as he was cleared cognitively, he jumped at the opportunity. He still had to take the odd nap, but it was helpful to be back at work and out among friends. Reyes’s brother also encouraged him to go to the gym. He introduced Reyes to a trainer, who also was studying to be an occupational therapist. On Reyes’s first meeting with her, he fell. “I fell down in front of her when I was taking the tour, but I picked myself back up. That was only the second time I had fallen, and it was the first time I picked myself up on my own strength.” Fast forward to today: Reyes now goes to the gym five times a week, and he walked a 5K just before the one-year anniversary of his stroke. He jokes, “They gave me a medal even though I came in last.” But ultimately, he knows he won. “It was a big thing for me to finish, because I’m still not the most stable. I could still fall down at any moment. Completing it puts your mind in a positive place like you can do things. With my stroke, I focused at first on what I can’t do; now, I focus on what I can do.” As for giving up things he previously enjoyed, he says it’s easy to do when you realize what’s at stake. “Death is a big motivator in my life right now. If [something I want to do] is a strike against me, then I guess I just have to give it up. And as much as I want to reach for the potato chips, I will reach for the pear. It has really changed.” Understanding how much his friends and family care about him also keeps him focused. “Beer and smoking, none of it is easy to give up. But it is easier when you understand that people care about you and you want to be there for them and for yourself. “I don’t recommend having a stroke to change your life, but if you have a traumatic thing, it’s best to try to find a way to deal with it in a positive way. I think the changes have been so positive that I don’t want to have my old life back.” Well, he admits, maybe the tacos. This story was reprinted with permission from SrokeSmart magazine, the official publication of the National Stroke Association. For more information, please visit http://www.strokesmart.org/ or http://www.stroke.org/

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The Burden of the Prior Authorization Process By Amanda Jamrogiewicz, CHCP

Not surprisingly, the PA burden is ultimately passed to the patient, with 92% of patients reporting care delays if their treatment requires PA. Average wait time for PA responses from health plans are at least one business day for 64%; 30% wait at least three business days. Perhaps most alarming is the high percentage of patients—21% ‘always or often,’ 57% ‘sometimes—that convey the correlation between PA and treatment abandonment. An alarming 92% report that PA can have a negative impact on patient clinical outcomes. Prior authorization (PA) requires healthcare providers to seek approval from a payer before certain medications or procedures will be covered. The PA process can be time-consuming and costly for clinicians, and may impact treatment strategies and patient care. In December 2017, the American Medical Association (AMA) fielded a web-based, 27-question survey distributed to 1,000 physicians.1 The national sample was comprised of 40% primary care physicians and 60% specialty physicians, all of whom provide 20 or more hours of patient care per week, and routinely complete prior authorizations (PAs) in their respective practices. The collective results of the survey indicated “the significant impact that prior authorization policies can have on both patients and physician practices.” From a physician impact standpoint, 84% of physicians claim that the burden associated with PA for both physicians and staff is very high. Moreover, 86% report that PA burdens have increased over the past five years, with 51% reporting a ‘significant’ increase. Results further demonstrated that the average total PAs per physician each week totaled 29.1, translating into approximately 14.6 hours spent by physicians/staff to complete the workload. A staggering 79% of physicians claim that they are ‘sometimes, often, or always’ required to repeat PAs for prescription medications, when a patient is stabilized on a treatment regimen for a chronic condition.

The PA burden is a recurring issue that can be found throughout all medical specialties; a recent survey conducted by the American College of Cardiology found that 78% of surveyed cardiologists cite the documentation and administrative burden associated with PA to be a barrier in terms of using newer therapies, such as angiotensin receptor/neprilysin inhibitors (ARNIs), non-vitamin K antagonist oral anticoagulants (NOACs), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors 2 At CMHC, we are dedicated to improving patient outcomes, which often includes addressing the inherent burden of the PA process. The 13th Annual Cardiometabolic Health Congress in Boston, taking place from October 24-27, will feature a satellite symposium: Mastering the Prior Authorization Process to Meet Patient Needs. This flipped-classroom approach will utilize infographics, patient case studies, resource center, and a clinician forum to post questions, which will be answered by expert clinicians in the field. References: 1) American Medical Association. “2017 AMA prior authorization physician survey.” 2017, available at https://www.ama-assn.org/sites/default/files/ media-browser/public/arc/prior-auth-2017.pdf, accessed May 1, 2018. 2) American College of Cardiology. “Barriers to new medications for cardiovascular disease: insights from CardioSurve.” Cardiology 46.2 (2017): 44-45


The fine line between ‘athlete’s heart’ and structural heart disease By Shpetim Karandrea, PhD

In many endurance athletes, increased left ventricular (LV) size, a mildly reduced left ventricular ejection fraction (LVEF), and lower resting heart rate develop as an adaptation to strenuous exercise. These nonpathological changes are termed as ‘athlete’s heart’, a term first used in the medical literature in 1953, although the first description of athletes with enlarged hearts dates back to the late 19th century. However, there is a fine line between athlete’s heart and true systolic dysfunction and pathological cardiomyopathy. Many professional athletes are diagnosed with cardiac pathology while still competing at the highest levels, while many others have died during games or competitions, or shortly after that, mostly due to dilated cardiomyopathy leading to sudden cardiac arrest. These findings have challenged the notion that excellent exercise capacity excludes pathological cardiomyopathy. In a very interesting study published recently in the European Heart Journal – Cardiovascular Imaging, Claessen and colleagues use realtime cardiac magnetic resonance imaging during exercise (ex-CMR) to distinguish between healthy endurance athletes (EA-healthy), patients with mild dilated cardiomyopathy (DCM), and athletes with known LV dysfunction and fibrosis (EA-fibrosis). The authors hypothesized that preserved exercise capacity does not exclude pathological damage and that LV contractile reserve is a reliable tool to differentiate between pathological and physiological remodeling. The subjects’ age, BMI, and

A yogurt a day? By Sarenka Smith

weight was similar in all groups. EA-healthy and DCM subjects had a resting LVEF < 52%, and as expected, healthy athletes had a greater exercise capacity than DCM patients. EA-fibrosis subjects, all highlevel former athletes diagnosed with LV fibrosis while still competing, had superior exercise capacity compared to both EA-healthy and DCM subjects, despite having significant LV pathology confirmed by imaging. The key difference was in the LV contractile reserve; both DCM and EAfibrosis subjects had diminished augmentation of LVEF and contractility during exercise compared to healthy athletes, and a cutoff value of Δ11.2% differentiated these subjects. The study showed that LV contractile reserve measured during exercise can be a useful diagnostic tool to distinguish athlete’s heart (or even benign physiological remodeling in non-athletes) from pathological LV remodeling. Exercise capacity alone did not exclude pathology, and it is possible that peripheral factors may play a role in preserving exercise performance despite a reduced LV augmentation and contractility, as seen in high-level retired athletes with known LV hypertrophy or ventricular arrhythmias. In addition, the study demonstrated abnormalities beyond LV; in both DCM and EA-fibrosis subjects the augmentation of right ventricular ejection fraction was also diminished during exercise. This study can have implications for individuals at risk of developing DCM, and may help to better dissect the fine line between DCM and athlete’s heart. Reference: Claessen, Guido, et al. “Exercise cardiac magnetic resonance to differentiate athlete’s heart from structural heart disease.” European Heart Journal-Cardiovascular Imaging (2018).

A recent study published in the American Journal of Hypertension suggests that higher yogurt intake is associated with lower cardiovascular disease (CVD) risk among hypertensive men and women. High blood pressure affects approximately one billion people across the globe and is one of the primary risk factors for cardiovascular disease. While clinical trials have shown that higher dairy consumption is associated with beneficial effects on CVD-related comorbidities such as hypertension, type 2 diabetes, and insulin resistance, yogurt itself may be also be independently related to CVD risk. The most current research findings included over 55,000 women (ages 30-55) with high blood pressure from the Nurses’ Health Study (NHS) and 18,000 men (ages 40-75) who participated in the Health Professionals Follow-Up Study (HPFS). Participants from these studies were asked to complete a mailed 61-item questionnaire to report normal dietary intake in the preceding year, and subsequently reported any interim physician-diagnosed events including myocardial infarction, stroke, and revascularization. NHS and HPFS participants were followed-up for incident CVD events for up to 30 years and 24 years, respectively. There were 3,300 and 2,148 total CVD cases (myocardial infarction, stroke, and revascularization) in the NHS and the HPFS,

respectively. In both cohorts, yogurt intake was inversely associated with CVD risk. Higher yogurt intake was associated with a 30% reduction in the risk of myocardial infarction among the NHS women, and a 19% reduction in the HPFS men. Among participants who consumed two or more servings of yogurt per week, NHS women had a 17% lower risk of myocardial infarction or stroke, while HPFS men has a 21% lower risk of these events compared to participants who consumed less than one serving of yogurt per month. When revascularization was added to the total CVD outcome variable, the risk estimates were reduced for both men and women, but remained significant. Participants that consumed yogurt regularly and also adhered to the DASH (Dietary Approaches to Stop Hypertension) diet, experienced the greatest cardiovascular risk reduction. This study showed the potential cardiovascular benefits of long-term yogurt intake in a large cohort of men and women with hypertension. Furthermore, CVD risk reduction may be greater when yogurt consumption is part of a diet rich in fiber, fruits, vegetables, whole grains, and lean meats. Reference: Buendia, Justin R., et al. “Regular yogurt intake and risk of cardiovascular disease among hypertensive adults.” American Journal of Hypertension 31.5 (2018): 557-565.

www.cardiometabolichealth.org

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PULSE BLOGS | Continued

A tailored letter improves the weight management in women with GDM By Sarenka Smith

Excessive weight gain during pregnancy and postpartum weight retention increases the risk of pregnancy complications for women and of developing type 2 diabetes in women with gestational diabetes mellitus (GDM. One of the strongest predictors of postpartum weight retention is excessive gestational weight gain (GWG), and promoting appropriate GWG within the Institute of Medicine (IOM) guidelines is advised in this high-risk population. In an effort to determine specific ways to improve GWG, a randomized controlled trial has evaluated the impact of a customized, tailored letter created through information provided by electronic health records (EHRs). The study further investigated whether a customized letter helped to moderate a multicomponent intervention regarding postpartum weight retention, among women diagnosed with GDM, a condition defined as any degree of glucose intolerance first recognized with the onset of pregnancy, and one that complicates approximately 7% of all pregnancies. The study surveyed 44 medical facilities, some of which delivered the usual standard

of care, others that used a tailored letter: termed a “multicomponent lifestyle intervention.” Through the use of data from EHRs, the tailored letter suggested an endof-pregnancy weight goal; the numbers were devised using pre-pregnancy BMI numbers and GWG from GDM diagnosis. In addition, the letter contained information about the current progress, lifestyle tips, and the risks of excessive weight gain during pregnancy. The guidelines recommended by the Institute of Medicine (IOM) were utilized to assess the number of women who met the suggested protocols. Results of the study demonstrated that the tailored letter showed a markedly significant increase in the number of women who met the IOM’s guidelines, with data reflecting that 72.6% of women in the intervention met this goal compared to 67.1% that received the usual care. In the intervention group, 36% of women met the end-of-pregnancy target weight goal, vs. 33.0% who had received the usual standard of care. Moreover, meeting the IOM’s guidelines helped mediate the effect of the intervention—the tailored letter—in lessening postpartum weight retention by 24.6%.

By Sarenka Smith

Through images scanned from the retinas of over 280,000 patients—specifically, retinal fundus images that showed the eye’s blood vessels—the pattern-recognizing algorithms, known as neural networks, were trained to recognize telltale signs of long-term health dangers and risks. While clinicians and medical professionals can use practices like blood tests to assess for risk factors, this technology differed in that the systems essentially taught themselves by reviewing enough data to learn patterns. The

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This trial demonstrated that the use of a tailored letter at the system-level has the potential to improve excess gestational weight gain and reduce the risk of complications for women with GDM. Reference: Hedderson, Monique M., et al. “A tailored letter based on electronic health record data improves gestational weight gain among women with gestational diabetes: the gestational diabetes’ effects on moms (GEM) cluster-randomized controlled trial.” Diabetes Care (2018): dc171133.

located other medical problems including diabetes, high blood pressure, high cholesterol, and some cancers during eye exams. Based on an eye scan, this algorithm was able to predict a person’s age within 3.26 years, smoking status with 71% accuracy, and blood pressure within 11 units of the upper number reported in their measurement.

Google predicts heart attacks through eyes By looking into the human eye, Google has developed an artificial intelligence software that can accurately predict a person’s risk of heart attack or stroke—creating a new opportunity and advancement in digital health technology and artificial intelligence.

The findings from the study further confirm the importance of personalized, customized medicine, which has the potential to significantly improve overall medical diagnosis and treatment. As a digital version of a patient’s clinical information, EHRs are designed to make information more accessible, and more readily available. EHRs are specifically built to share information— not only with other healthcare providers and clinicians, but also other organizations. A critical component of the rapidly emerging field of digital technology in medicine, EHRs is a longitudinal, complete representation of a patient’s chart and care.

deep-learning models trained on the data predicted cardiovascular risk factors that were previously considered unquantifiable in retinal images. Researchers from Google have used similar machine-learning methods to determine diabetic retinopathy, an eye disease and primary cause of blindness. In the most recent study, the researchers used an additional machine-learning technique termed “soft attention,” which helped identify which specific parts of the image were most accurate and instrumental in spurring the algorithms’ predictions. Other studies and findings have confirmed that the retina can serve as a useful passageway into the body, as physicians have

Due to the algorithm’s efficacy in assessing the aforementioned factors, researchers used data from a set of 150 patients: all of whom had suffered major cardiovascular events within five years of the scan. When the algorithm was presented with two retina images, and asked to predict which one would suffer a major cardiac event or stroke, it predicted the correct scan with 70% accuracy. The findings demonstrate that machine-learning is not only transforming the ways in which the body is studied and illnesses are diagnosed, but also generating a more complete picture of human health. Moreover, the data indicates that deep convolutional neural networks, optimized for images, can generate highly accurate algorithms that diagnose several forms of chronic disease. Reference: Poplin, Ryan, et al. “Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning.” Nature Biomedical Engineering 2.3 (2018): 158.


Type 2 Diabetes

PPARγ AGONIST LYN KINASE ACTIVATOR

PHASE III

GLUCOKINASE ACTIVATOR

PHASE II

LONG-ACTING AMYLIN

DRUG PIPELINE

FGFR1/KLB ANTAGONIST

PHASE I GLP-1R/GCGR/GIPR TRIPLE AGONIST

summaries

GLP-1 RA

GLP-1R/GIPR DUAL AGONIST DUAL SGLT-1/2 INHIBITOR

GLP-1R/GCGR DUAL AGONIST

Source: ClinicalTrials.gov

Heart Failure

MOA PARTIAL ADENOSINE A1 RA CHYMASE INHIBITOR

PHASE II

NELADENOSON BIALANATE BAY1142524

NITROXYL (HNO) DONOR

CXL-1427

ORAL SGC STIMULATOR

IW-1973

ORAL SGC STIMULATOR

VERICIGUAT

HFrEF CARDIAC MYOSIN ACTIVATOR

PHASE III

ADENOVIRUS 5 ENCODING HUMAN ADENYLYL CYCLASE 6

PHASE I

HFpEF

APELIN RECEPTOR (APJ) AGONIST

PHASE II

PHASE III

INSULIN

Drug

TRANSCATHETER DEVICE ANGIOTENSIN-RECEPTOR/NEPRILYSIN DUAL INHIBITOR SGLT-2 INHIBITOR

OMECAMTIV MECARBIL RT-100

AMG 986

Obesity PHASE III PHASE II PHASE I

IASD SACUBITRIL/VALSARTAN

METAP2 INHIBITOR DUAL SGLT-1/2 INHIBITOR HUMAN MONOCLONAL ANTIBODY PEPTIDE YY HORMONE ANALOGUE

EMPAGLIFLOZIN

FGF 21 ANALOGUE HFpEF = heart failure with preserved ejection fraction

HFrEF = heart failure with reduced ejection fraction

GLUCAGON ANALOGUE

Hypercholesterolemia

AMYLIN ANALOGUE

MOA

PHASE II

Drug ANGPTL3 INHIBITOR

LIVER ACC AND HMG-COA SYNTHASE INHIBITOR

EVINACUMAB

GLP-1R/GIPR/GCGR TRIPLE AGONIST GLP-1R/GCGR DUAL AGONIST

GEMCABENE

GLP-1 RA ATP CITRATE LYASE (ACL) INHIBITOR

PHASE III

ACL INHIBITOR/CHOLESTEROL ABSORPTION INHIBITOR SIRNA REDUCTION OF PCSK9 ACTIVITY

BEMPEDOIC ACID BEMPEDOIC ACID/EZETIMIBE COMBINATION PILL INCLISIRAN

www.cardiometabolichealth.org

19


CARDIOMETABOLIC

NEWS

FDA panel recommends approval of a 90-day implantable CGM

Voting unanimously in favor, an FDA advisory committee has recommended approval for a continuous glucose monitor (CGM) that can be implanted in the upper arm for 90 days. The device, Eversense by Senseonics, is paired with a small transmitter that sends readings to a smartphone app: including real-time glucose information with readings, trend data, and alerts regarding hypoglycemia and hyperglycemia. Data from the PRECISE II study showed that the device provided accurate glucose readings throughout the intended 90-day period in individuals with type 1 or type 2 diabetes. Mean absolute relative difference was 8.8%, which was significantly lower than the pre-specified goal of 20% to show accuracy, and 91% of sensors were functional through day 90. The overall accuracy of the Eversense system was 93.3%, and detected 93% of hypoglycemic and 96% of hyperglycemic events. However, 14% of hypoglycemic and 6% of hyperglycemic alerts were false positives. The device is the first FDA-approved implantable CGM, requires two fingerstick calibrations per day and is intended as an adjunct to self-monitoring of blood glucose in making treatment decisions. Reference: https://www.ncbi.nlm.nih.gov/pubmed/29381090

FDA approves first interoperable CGM

The FDA has authorized the marketing of the first integrated continuous glucose monitoring (iCGM) system to determine blood glucose in adults and children (â&#x2030;Ľ 2 years of age) with diabetes. The Dexcom G6 is the first type of CGM system that can be used with other compatible electronic interfaces and medical devices, including insulin pumps, medical apps, and other devices designed for diabetes management. Unlike the earlier Dexcom models, Dexcom G6 does not require fingerstick calibrations. FDA approved the device after analyzing data from two clinical studies, which compared the accuracy of the device to a laboratory test for blood glucose. These studies included 324 adults and children with diabetes, which were evaluated during multiple clinical visits over a 10-day period, and no serious events were reported. In addition, the device has an updated sensor probe that minimizes the interference with acetaminophen, which can cause erroneously high glucose readings in CGM systems for people taking the drug. The FDA has classified this new type of device as a class II, which has a lower risk classification and regulatory burden than class III devices;

20

www.cardiometabolichealth.org

potentially enabling developers of future iCGM systems to bring products to market more easily, rapidly, and effectively. Reference: https://www.ncbi.nlm.nih.gov/pubmed/29715340

FDA approves sodium zirconium cyclosilicate for the treatment of hyperkalemia

FDA has approved sodium zirconium cyclosilicate, formerly known as ZS-9 (Astrazeneca), for the treatment of hyperkalemia, a serious condition in which serum potassium levels are elevated. Hyperkalemia is associated with increased risk of mortality and is prevalent and recurrent in patients who suffer from heart failure (HF), chronic kidney disease (CKD), hypertension or diabetes. Common medications that treat HF and hypertension, such as RAAS inhibitors, can cause hyperkalemia, which may require the discontinuation or down-titration of RAAS inhibitor therapy and thus jeopardize patient health. Sodium zirconium cyclosilicate selectively traps potassium through the GI tract and exchanges it for sodium, allowing for the quick removal of excess potassium from the bloodstream. FDA approval was based on two randomized, placebo-controlled trials and two open label follow-up studies that enrolled people with hyperkalemia and important comorbidities, including HF, CKD, diabetes, or on RAAS inhibitor therapy at baseline. In these studies, sodium zirconium cyclosilicate effectively lowered serum potassium levels with a rapid (1 hour) onset of action. Median time required to return serum potassium levels to normal (<5.5 mEq/L) was 2.2 hours, and most (92%) of patients reached normal serum potassium levels within 48 hours. The most serious treatment-related adverse event in these studies was edema, reported in 8-11% of patients. Reference: https://www.accessdata.fda.gov/drugsatfda_ docs/label/2018/207078s000lbl.pdf

SGLT-2 inhibitors and GLP-1 RAs associated with improved survival in T2D

A recent meta-analysis aiming to compare the effects of three classes of antihyperglycemic medications on mortality and cardiovascular endpoints, showed that SGLT-2 inhibitors and GLP-1 receptor agonists, but not DDP-4 inhibitors are associated with lower mortality in type 2 diabetics. Trials that enrolled patients with type 2 diabetes and had a follow-up time of at least 12 weeks were

selected, with a total of 176,310 randomized individuals from 236 trials. Patients that received an SGLT-2 inhibitor or a GLP-1 receptor agonist had a 1% or 0.6% lower rate of all-cause mortality, respectively, compared to control groups. Patients treated with either an SGLT-2 inhibitor or a GLP-1 receptor agonist had a lower all-cause mortality compared to patients treated with a DDP-4 inhibitor. Furthermore, patients that received either SGLT-2 inhibitor or a GLP-1 receptor agonist were less likely to die from cardiovascular causes compared to patients treated with a DDP-4 inhibitor or placebo. Half of the patients included in this analysis were from the 9 major cardiovascular outcome trials (CVOTs) of these three drug classes in type 2 diabetes patients. According to the meta-analysis, GLP-1 receptor agonists were associated with a higher rate of adverse events leading to trial withdrawal compared to SGLT-2 inhibitors or DDP-4 inhibitors. Reference: https://www.ncbi.nlm.nih.gov/pubmed/29677303

Canakinumab fails to prevent progression from prediabetes to diabetes

The CANTOS study, in addition to evaluating the role of canakinumab on cardiovascular outcomes, also tested the hypothesis that canakinumab treatment reduces the risk of incident type 2 diabetes. Canakinumab is a human monoclonal antibody that targets interleukin-1 (IL-1), which is upstream of IL-6 and hs-CRP, thereby decreasing IL-1 signaling and consequent inflammation. The trial enrolled a total of 10,061 patients, out of which 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) were normoglycemic. Baseline concentrations of hs-CRP and IL-6 predicted the risk of incident T2D in patients without diabetes at baseline, and this association was statistically significant after adjusting for potential confounding factors (BMI, family history of diabetes, smoking, exercise, alcohol use, and T2D therapy). In addition, canakinumab was found to have similar efficacy for major cardiovascular events and reduction of inflammation in patients with and without diabetes. However, despite dose-dependent reductions in hs-CRP and IL-6, canakinumab treatment (50mg, 150mg, and 300mg) did not reduce the incidence of new-onset T2D compared to placebo over a 5-year follow-up period. Modest reductions in HbA1c in prediabetic patients were observed with canakinumab treatment during the first 6-9 months, however, this effect was attenuated over time and not statistically significant after 48 months. Similar effects were seen in patients with existing T2D or normoglycemia at baseline, and no consistent effects were observed for fasting plasma glucose across all groups. Reference: https://www.ncbi.nlm.nih.gov/pubmed/29544870

PCSK9 inhibitor alirocumab reduces CV events after ACS Results from the phase III ODYSSEY Outcomes trial, demonstrated that the PCSK9 inhibitor alirocumab reduced


cardiovascular events in patients with a recent history of acute coronary syndrome (ACS) and persistently high LDL cholesterol despite high-intensity statin therapy. This trial enrolled nearly 19,000 patients that had ACS within one month to one year enrolling in the study, and the primary outcome was the occurrence of cardiovascular events (composite endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization) during a mean follow-up time of 34 months. After this follow-up time, LDL-C levels were 53.3 mg/dL in the alirocumab group compared with 101.4 mg/ dL in the placebo group. Patients treated with alirocumab had a 15% reduction of the primary composite endpoint compared to the placebo group (9.5% vs. 11.1% respectively); with all individual components of the primary endpoint significantly reduced except CHD death. All-cause mortality was significantly reduced in the alirocumab treatment (3.5% vs. 4.1% in placebo), however, no significant difference was observed between groups for cardiovascular death. The most robust outcomes were observed in patients with a baseline LDL-C ≥100 mg/dL; in these patients, the primary endpoint was reduced by 24%, and CHD death, cardiovascular death, and all-cause mortality were reduced by 28%, 31%, and 28% respectively compared to placebo. The study was the first to report a mortality benefit with alirocumab, and is expected to continue patient follow-up for up to 10 years to determine whether these benefits continue after treatment cessation. Alirocumab was well tolerated, and minor injection site reactions were the only significant treatment-related adverse events reported (3.1 % in alirocumab group vs. 2.1 % in placebo). Reference: https://www.ncbi.nlm.nih.gov/pubmed/29701178

Barbershop-based intervention reduces hypertension in black men

A new study indicates that linking health promotion by barbers to pharmacist-directed drug therapy has helped almost two thirds of black men, all of whom were diagnosed with uncontrolled hypertension, reach the new U.S. blood pressure (BP) targets. In this randomized trial, 319 black male patrons from 52 black-owned barbershops with high BP (≥140 mmHg) were enrolled, and barbershops were assigned to either a pharmacist-led intervention (in which barbers encouraged meetings in barbershops with specialty-trained pharmacists who regularly checked BP, monitored creatinine and electrolytes, prescribed medications, and sent progress notes to primary care providers) or to an active control approach (in which barbers encouraged lifestyle modification and doctor appointments). At baseline, mean systolic blood pressure (SBP) was 152.8 mmHg in the intervention group, and 154.6 mmHg in the control group. The pharmacist-led intervention resulted in a significant decrease in SBP (125.8 mmHg vs. 145.4 mmHg) compared to control group at 6 months. Target blood pressure of less than 130/80 mmHg was achieved in 63.6% of the pharmacist-led intervention

group, compared to only 11% in the control group. In the intervention group, retention rate was 95% with few adverse events. This newly conceived model for chronic-disease management effectively delivers interventions to the places in which people live and work, and this study demonstrated that using community outreach may be beneficial to combat cardiovascular disease risk factors. Reference: https://www.ncbi.nlm.nih.gov/pubmed/29527973

Semaglutide may help obese people lose weight

A recent study indicates that GLP-1 receptor agonist semaglutide may help obese people who do not have diabetes lose weight. Semaglutide, which was FDA-approved in 2017 for the treatment of type 2 diabetes, was previously shown to be beneficial for weight reduction in type 2 diabetics as part of the cardiovascular outcomes trial SUSTAIN-6. In this study, 957 subjects with a body mass index (BMI) of at least 30 kg/m2 and without diabetes were randomized to seven different groups; five groups received different doses of semaglutide injections (between 0.05 – 0.4 mg) once-weekly, the sixth group received a placebo, and the seventh group received 3 mg liraglutide, another GLP-1 receptor agonist currently approved for weight loss in obese people. After one year, semaglutide treatments led to a significant weight loss compared to placebo, and this effect was dose dependent; patients that received 0.05 mg semaglutide lost an average of 6% of their body weight, with this effect increasing to 8.6%, 11.2%, and 13.8% for the 0.1 mg, 0.3 mg, and 0.4 mg semaglutide groups, respectively. Subjects receiving liraglutide lost an average of 7.8% of their body weight, while those in the placebo group lost only 2.3% on average. Furthermore, 65% of patients that received 0.4 mg semaglutide lost at least 10% of their body weight (compared to 10% with placebo and 34% with liraglutide). Semaglutide injections were generally well tolerated and the most common adverse events were mild to moderate nausea. Reference: O’Neil, P. M., A. L. Birkenfeld, and B. McGowan. “A randomized, Phase II, placebo-and active-controlled dose-ranging study of semaglutide for treatment of obesity in subjects without diabetes.” ENDO (2018): 17-20.

Biomarkers improve CV risk assessment in older adults

Global CVD risk assessment is an integrated approach to evaluate the total risk of developing CVD over a given period (usually 10 years) based on the presence of several risk factors, including hypertension, type 2 diabetes, dyslipidemia, smoking, family history, obesity, age, and male sex. The pooled cohort equation (PCE) is recommended to estimate the 10-year atherosclerotic CVD risk, however, it relies heavily on traditional risk factors and may have limitations on predicting global CVD risk. Several studies have shown that the use of biomarkers -- such as cardiac troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP), and high sensitivity C-reactive

protein (hs-CRP) -- in addition to current methods may improve CVD risk assessment. The Atherosclerosis Risk in Communities study evaluated whether the addition of biomarkers (troponin, NT-proBNP, and hs-CRP) to PCE improves the incidence of global CVD events (defined as coronary heart disease, myocardial infarction, CV revascularization, stroke or heart failure) in older adults (mean age of 75.7 years) without CVD or heart failure at baseline. The addition of each biomarker independently improved risk prediction compared to PCE alone, and this effect was greater with all three biomarkers combined during a median follow-up of approximately 4 years. The most common CVD event was incident heart failure, followed by coronary heart disease and stroke. A “lab model” including the three biomarkers as well as age, race, and gender also led to improved risk assessment compared to the PCE model alone. The findings of this study provide additional support for the use of these biomarkers in addition to the PCE for global CVD risk assessment, and may have future implications for CVD prevention in older adults. Reference: https://www.ncbi.nlm.nih.gov/pubmed/29535064

ACP recommends less aggressive HbA1c targets

In March of this year, the American College of Physicians (ACP) issued a guidance statement on HbA1c targets for adults with type 2 diabetes (T2D), recommending a target HbA1c goal between 7-8% to maintain optimal glucose control. This is higher than what’s recommended by the American Diabetes Association (ADA) or the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE). ADA recommends a goal of <7% for HbA1c, even advocating more stringent goals (such as <6.5%) for certain patients with a low risk of hypoglycemia. The AACE/ACE guidelines recommend keeping HbA1c levels at ≤ 6.5% for most patients with low-risk of side effects. The statement from ACP also recommends the individualization of T2D therapy, deintensification of therapy for patients that achieve HbA1c levels of less than 6.5%, and controlling symptoms rather than focusing on specific HbA1c goals in patients with a life expectancy of less than 10 years. One of the main ideas behind this statement is to balance the benefits of lowering blood glucose with potential risks, such as important side effects (like hypoglycemia and weight gain), costs, and overall patient burden. In response, the ADA issued its own statement in which it restates its support behind an HbA1c goal of <7%, while also emphasizing the need for individualized therapy. While establishing relevant HbA1c goals is important, balancing the risk-benefit profile of pharmacotherapies with patientlevel factors is key to minimizing the longterm complications of T2D, and clinicians should always use their best judgment to guide therapeutic decisions. References: https://www.ncbi.nlm.nih.gov/pubmed/29507945 http://www.diabetes.org/newsroom/press-releases/2018/ada-acp-guidance-response.html

www.cardiometabolichealth.org

21


With type 2 diabetes, life can change in a heartbeat

THE MORNING ON THE BEACH WAS PERFECTâ&#x20AC;Ś

Reference: 1. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes. Diabetes Care. 2006;29:1220-1226.

The Treating to New Targets (TNT) study included 1501 patients with diabetes and CHD, with LDL cholesterol levels <130 mg/dL. Patients were randomized to receive either atorvastatin 10 mg/day (n=753) or 80 mg/day (n=748) and were followed for a median of 4.9 years. The primary endpoint was the time to first major cardiovascular event.

a


…UNTIL

WASN’T

You set targets for A1C, LDL cholesterol, and blood pressure, but are your patients still at CV risk? In the TNT study, even with statin treatment, 14% to 18% of patients with diabetes experienced a CV event.1,a Make the connection at

heartoftype2PRO.com

Novo Nordisk is a registered trademark of Novo Nordisk A/S. ©2017 Novo Nordisk Printed in the U.S.A. USA17GLP00580 April 2017


DIABETES by numbers A healthy lifestyle

Saturated fat

may be more harmful to the

liver

is crucial to

preventing diabetes

and heart disease. A study surveying

3,679 US

adults without diabetes found that

only 3.1%

of participants met the combined recommended diet and physical activity goals.

than unsaturated fat or simple sugars. In a study of

38 overweight people overfed

1000 extra Kcal/day of saturated, unsaturated fats, or simple sugars for 3 weeks, extra calories from saturated fat increased

met the fruit, vegetable, and dairy recommendations.

liver triglyceride content by 55%. Excess unsaturated fats increased this content by 15%, and sugars by 33%. Decreas-

met the physical activity and the weight loss/maintenance goals, respectively.1

3.https://www.ncbi.nlm.nih.gov/pubmed/29844096

21%, 29%, and 13% 37.8% and 58.6%

ing intakes of saturated fat may reduce the risk of non-alcoholic fatty liver.3

1.https://www.ncbi.nlm.nih.gov/pubmed/29500166

A large Korean study showed that

cancer

may increase the risk of

type 2 diabetes. The study included

524,089

men and women with no cancer or diabetes at baseline, followed-up for 7 years.

15,130

participants developed cancer and

26,610

developed type 2 diabetes. Cancer was associated with a

1.35X greater risk

for developing type 2 diabetes. Pancreatic, kidney, and liver cancers were associated with the highest diabetes risk, increasing this risk by

5.15X, 2.06X, and 1.95X.

2

2.https://www.ncbi.nlm.nih.gov/pubmed/29879271

24

www.cardiometabolichealth.org

A recent study published in Diabetes Care shows the staggering economic impacts of diabetes in the US in 2017. The cost of diabetes increased by 26% from 2012-2017, and now costs the US economy $327 billion â&#x20AC;&#x201C; including

$237 billion

in direct medical costs and

$90 billion

in lost productivity. Diabetes care accounts for 1 in 4 US healthcare dollars. Diabetics spend an average of $16,7500 in medical care a year, and have medical costs that are

2.3X higher

than non-diabetics.5 Controlling blood glucose, blood pressure, and cholesterol are important for the long-term management of type 2 diabetes. In a retrospective study of 53,120 patients with type 2 diabetes selected from the Veterans Affairs (VA) medical records, achieving treatment goals of

HbA1c <7.0%, LDL-C <100 mg/dL, and BP <140/90 mmHg (triple-goal achievement) was associated with a decreased risk of microvascular and macrovascular complications, and all-cause mortality, with 13,507 patients achieving all three of these targets.4

4.https://www.ncbi.nlm.nih.gov/pubmed/29596940

5.https://www.ncbi.nlm.nih.gov/pubmed/29567642

Food insecurity and living in areas with low physical access to nutritious foods may complicate symptom control in diabetics. A longitudinal study that followed 391 diabetics for a total of 37 months, showed that food insecurity is associated with a 0.6%, or 6.6 mmol/mol higher HbA1c compared to participants that were food secure. Living in an area with low food access was not associated with a change in HbA1c.6 6.https://www.ncbi.nlm.nih.gov/pubmed/29555650


CVD by numbers Patients admitted in hospital for heart failure (HF) have an increasing number of non-cardiovascular comorbidities. In a study using data from

207,984

patients in the Get with the Guidelines-HF registry, 30% of patients had 1 comorbidity, 27% had 2, and 25% had 3 or more. The number of HF patients with 3 or more comorbidities grew 18-29% from

2005 to 2014,

which increased their risk for 30-day mortality.

Biomarkers such as B-type natriuretic peptide (BNP) may be an independent predictor of mortality in people with and without heart failure (HF). In a study of

30,487

patients, including 38% with HF, BNP levels and age were independently associated with mortality. A BNP level of 400 pg/ml was associated with a

21%

increased risk of mortality in people with HF, and with a

19%

increased mortality risk in those without HF.3

5.https://www.ncbi.nlm.nih.gov/pubmed/29632217

1.https://www.ncbi.nlm.nih.gov/pubmed/29793934

3.https://www.ncbi.nlm.nih.gov/pubmed/29747827

Work stress may exacerbate cardiometabolic disease in men with coronary heart disease (CHD), diabetes, or stroke. In a study of

Acute kidney injury (AKI) is independently associated with a higher risk of heart failure (HF), per a retrospective study of 146,941 hospitalized adults admitted at 21 hospitals and followed-up for 365 days. The 31,245 patients that experienced AKI were

3,441

men with cardiometabolic disease, age-standardized mortality was

1.5X higher

in men that reported job strain than in those without. The mortality rate associated with work stress,

149.8 per 10,000

person-years, was clinically significant and independent of traditional risk factors.2

Total direct and indirect costs of cardiovascular disease are projected to grow from $555 billion in 2015 to $1.1 trillion by 2035. This is not including informal caregiving costs. A recent study estimated that the burden of informal caregiving for CVD patients is significant; estimated at $61 billion in 2015, this cost is expected to increase to $128 billion by 2035, which would add an additional 11% to costs attributable to CVD.5

1.4X

more likely to have subsequent HF post-discharge compared to matched-controls that did not experience AKI.4

Increasing vegetable intake is associated with a decreased risk of subclinical atherosclerosis in older adult women. In a study of 954 women without ASCVD, participants that consumed

â&#x2030;Ľ3 servings

of vegetables each day had a

4.6-5% lower

mean carotid artery intima-media thickness compared to women that consumed

<2 servings/day.

6

6.https://www.ncbi.nlm.nih.gov/pubmed/29618474

4.https://www.ncbi.nlm.nih.gov/pubmed/29773712

2.https://www.ncbi.nlm.nih.gov/pubmed/29884468

www.cardiometabolichealth.org

25


Familial chylomicronemia syndrome (FCS) is a hereditary enzymatic deficiency characterized by the buildup of chylomicrons (chylomicronemia), which leads to severe hypertriglyceridemia, a hallmark of the disease.1 Chylomicronemia also brings increased risk of morbidity and mortality, including episodes of abdominal pain and the threat of unpredictable and potentially fatal acute pancreatitis.2,3


FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS) CAN BE CLINICALLY DIAGNOSED. LOOK FOR ITS SIGNS AND SYMPTOMS.4,5,a

1 2 3

SEVERE, REFRACTORY HYPERTRIGLYCERIDEMIA6,7 • Fasting triglycerides >880 mg/dL (10 mmol/L) • Minimally or not responsive to standard therapies

CLINICAL HISTORY1,2 • Acute pancreatitis and/or abdominal pain (may be recurrent or chronic), without other explainable causes

ABSENCE OF SECONDARY CAUSES OF HYPERTRIGLYCERIDEMIA 8,9 • Excess alcohol intake, uncontrolled diabetes, certain medications, or other medical conditions

FCS Visit FCSFocus.com for comprehensive FCS education and resources.

Proposed diagnostic criteria.

a

References: 1. Brahm et al. Nat Rev Endocrinol. 2015;11:352-362. 2. Brunzell et al. The Metabolic and Molecular Bases of Inherited Disease. 2001:2789-2816. 3. Stroes et al. Atheroscler Suppl. 2017;23:1-7. 4. Jacqueline. https://globalgenes.org/raredaily/my-journey-to-find-hope-with-familial-chylomicronemia-syndrome. Accessed January 24, 2018. 5. Davidson et al. Expert Rev Cardiovasc Ther. 2017;15(5):415-423. 6. Tremblay et al. Front Genet. 2014;5:90. 7. Reiner et al. Eur Heart J. 2011;32(14):1769-1818. 8. Miller et al. Circulation. 2011;123(20):2292-2333. 9. Berglund et al. J Clin Endocrinol Metab. 2012;97(9):2969-2989.

© 2018. Akcea Therapeutics, Inc. All rights reserved. FCS-00310 01/2018


Metabolic abnormalities, heart and kidney disease

Editors-in-Chief

Peter A. McCullough, Dallas, TX Claudio Ronco, Vicenza Adam T. Whaley-Connell, Columbia, MO

Affiliated with

CardioRenal Medicine explores the mechanisms by which obesity and other metabolic abnormalities promote the pathogenesis and progression of heart and kidney disease (cardiorenal metabolic syndrome). It provides an interdisciplinary platform for the advancement of research and clinical practice, focussing on translational issues. The journal addresses a multidisciplinary audience consisting of nephrologists, cardiologists, nutritionists, endocrinologists, physiologists and general internists.

www.karger.com/crm

KI18262

Listed in bibliographic services, including: PubMed/MEDLINE, Web of Science, Science Citation Index Expanded, Google Scholar


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CMHC - Cardiometabolic Chronicle July 2018  

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